Substituted Azaspiro(4.5)Decane Derivatives

ABSTRACT

The invention relates to substituted spirocyclic cyclohexane derivatives which have an affinity for the μ opioid receptor and the ORL1 receptor, processes for the preparation thereof, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.

The present invention relates to substituted spirocyclic cyclohexane derivatives which have an affinity for the μ opioid receptor and the ORL1 receptor, processes for the preparation thereof, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.

Spirocyclic cyclohexane derivatives which have an affinity for the μ opioid receptor and the ORL1 receptor are known in the prior art. In this connection reference may be made to, for example, the full scope of WO2004/043967, WO2005/063769, WO2005/066183, WO2006/018184, WO2006/108565, WO2007/124903, WO2008/009416, WO2008/101659, WO2009/118169 and WO2009/118173.

However, the known compounds are not satisfactory in all respects and there is a need for further compounds with comparable or better properties.

Thus, in suitable binding assays the known compounds sometimes show a certain affinity for the hERG ion channel, for the L-type calcium ion channel (phenylalkylamine, benzothiazepine, dihydropyridine binding sites) or for the sodium channel in the BTX assay (batrachotoxin), which can in each case be interpreted as an indication of cardiovascular side effects. Numerous of the known compounds furthermore show only a low solubility in aqueous media, which can have an adverse effect, inter alia, on the bioavailability. The chemical stability of the known compounds moreover is often only inadequate. Thus, the compounds sometimes do not show an adequate pH, UV or oxidation stability, which can have an adverse effect, inter alia, on the storage stability and also on the oral bioavailability. The known compounds furthermore in some cases have an unfavourable PK/PD (pharmacokinetic/pharmacodynamic) profile, which can manifest itself e.g. in too long a duration of action.

The metabolic stability of the known compounds also appears to be in need of improvement. An improved metabolic stability can indicate an increased bioavailability. A weak or non-existent interaction with transporter molecules involved in the uptake and excretion of drugs is also to be evaluated as an indication of an improved bioavailability and at all events low drug interactions. Furthermore, the interactions with the enzymes involved in the breakdown and excretion of drugs should be as low as possible, since such test results likewise indicate that at all events low drug interactions or none at all are to be expected.

The known compounds furthermore sometimes show an only low selectivity for the kappa opioid receptor, which is responsible for side effects, in particular dysphoria, sedation, diuresis. The known compounds moreover sometimes show a very high affinity for the μ opioid receptor, which appears to be connected with other side effects, in particular respiratory depression, constipation and addiction.

The invention is based on the object of providing compounds which are suitable for pharmaceutical purposes and have advantages over the compounds of the prior art.

This object is achieved by the subject matter of the claims.

It has been found, surprisingly, that substituted spirocyclic cyclohexane derivatives which have an affinity for the μ opioid receptor and the ORL1 receptor can be prepared.

The invention relates to compounds of the general formula (1)

-   -   wherein     -   Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently         of each other are chosen from the group consisting of —H, —F,         —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H,         —C(═O)—OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH,         —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀,         —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂,         —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀,         —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂;         preferably in each case independently of each other are chosen         from the group consisting of —H, —F, —C₁₋₈-aliphatic,         —C₁₋₈-aliphatic-NHC₁₋₈-aliphatic,         —C₁₋₈-aliphatic-N(C₁₋₈-aliphatic)₂, —S—C₁₋₈-aliphatic, —S-aryl,         -aryl, —C₁₋₈-aliphatic-aryl; or Y₁ and Y₁′, or Y₂ and Y₂′, or Y₃         and Y₃′, or Y₄ and Y₄′ together represent ═O;     -   X₁, X₁′, X₂, X₂′, X₃ and X₃′ in each case independently of each         other represent —H, —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —SR₅,         —SO₂R₅, —S(═O)₂OR₅, —CN, —COOR₅, —CONR₅, —NR₆R₇, or —R₀; or X₁         and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O;     -   or X₁ and X₂ or X₂ and X₃ together represent —(CH₂)₂₋₆—, wherein         individual hydrogen atoms can also be replaced by —F, —Cl, —Br,         —I, —NO₂, —CF₃, —OR₅, —CN or —C₁₋₆-aliphatic;     -   or X₁ and X₁′ or X₂ and X₂′ or X₃ and X₃′ together represent a         C₃₋₆-cycloaliphatic, wherein individual hydrogen atoms can also         be replaced by —F, —Cl, —Br, —NO₂, —CF₃, —OR₅, —CN or         —C₁₋₆-aliphatic;     -   R₀ in each case independently represents —C₁₋₈-aliphatic,         —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl,         —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl,         —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic,         —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl;     -   R₁ and R₂ independently of each other represent —H or —R₀; or R₁         and R₂ together represent —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₈CH₂CH₂— or         —(CH₂)₃₋₆—;     -   R₃ represents —R₀;     -   R₄ represents H or —Z—R₁₁,         -   wherein         -   Z can be absent or —C(═O)—, —S(═O)— or —S(═O)₂—, and         -   R₁₁ represents —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or             —C₁₋₃-alkyl-C₃₋₆-cycloalkyl, wherein in the C₃₋₆-cycloalkyl             group a ring carbon atom can be replaced by an oxygen atom             and —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or             —C₁₋₃-alkyl-C₃₋₆-cycloalkyl can be unsubstituted, mono- or             polysubstituted with substituents independently of each             other selected from the group consisting of —F, —Cl, —Br,             —I, —ON, —OH, —SH, —O—C₁₋₃-alkyl and —S—C₁₋₃-alkyl, wherein             —C₁₋₃-alkyl can be substituted by one or more substituents             from the group consisting of —F, —Cl, —Br, —I, —CN, —OH,             —OCH₃, —SH and —SCH₃;     -   R₅ in each case independently represents —H or —R₀;     -   R₆ and R₇ independently of each other represent —H or —R₀; or R₆         and R₇ together represent —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₁₀CH₂CH₂— or         —(CH₂)₃₋₆—;     -   R₈ represents —H, —R₀ or —C(═O)R₀;     -   R₁₀ represents —H or —C₁₋₆-aliphatic;     -   wherein     -   “aliphatic” in each case is a branched or unbranched, saturated         or a mono- or polyunsaturated, unsubstituted or mono- or         polysubstituted, aliphatic hydrocarbon radical;     -   “cycloaliphatic” in each case is a saturated or mono- or         polyunsaturated, unsubstituted or mono- or polysubstituted,         alicyclic, mono- or multicyclic hydrocarbon radical, the number         of ring carbon atoms of which is preferably in the stated range         (i.e. “C₃₋₈-” cycloaliphatic preferably has 3, 4, 5, 6, 7 or 8         ring carbon atoms);     -   wherein with respect to “aliphatic” and “cycloaliphatic”, “mono-         or polysubstituted” is understood as meaning substitution once         or several times of one or more hydrogen atoms, e.g.         substitution once, twice, three times or completely by         substituents independently of each other chosen from the group         consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀,         —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀,         —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,         —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,         —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,         —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀,         —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂;     -   “aryl” in each case independently represents a carbocyclic ring         system having at least one aromatic ring, but without hetero         atoms in this ring, wherein the aryl radicals can optionally be         fused with further saturated, (partially) unsaturated or         aromatic ring systems and each aryl radical can be unsubstituted         or mono- or polysubstituted, wherein the substituents on aryl         can be identical or different and can be in any desired and         possible position of the aryl;     -   “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic         radical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the         hetero atoms are identical or different and are nitrogen, oxygen         or sulfur and the heterocycle can be unsubstituted or mono- or         polysubstituted; wherein in the case of substitution on the         heterocycle the substituents can be identical or different and         can be in any desired and possible position of the heteroaryl;         and wherein the heterocycle can also be part of a bi- or         polycyclic system;     -   wherein with respect to “aryl” and “heteroaryl”, “mono- or         polysubstituted” is understood as meaning substitution once or         several times of one or more hydrogen atoms of the ring system         by substituents chosen from the group consisting of —F, —Cl,         —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH,         —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)—N(R₀)₂, —OH,         —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀,         —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀,         —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻,         —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀,         —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂; wherein N ring atoms         optionally present can in each case be oxidised (N-oxide);     -   in the form of an individual stereoisomer or mixture thereof,         the free compounds and/or their physiologically acceptable salts         and/or solvates.

Where various radicals are combined, for example Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′, and where radicals on substituents thereof are combined, such as e.g. —OR₀, —OC(═O)R₀, —OC(═O)NHR₀, a substituent, e.g. R₀, can assume different meanings for two or more radicals, for example —OR₀, —OC(═O)R₀, —OC(═O)NHR₀, within a substance.

The compounds according to the invention show good binding to the ORL1 receptor and/or the μ opioid receptor, preferably to the ORL1 receptor and the μ opioid receptor.

The compounds according to the invention preferably have a K_(i) value on the μ opioid receptor of at most 500 nM, more preferably at most 100 nM or at most 50 nM, still more preferably at most 10 nM, most preferably at most 1.0 nM and in particular at most 0.5 nM.

Methods for determination of the K_(i) value on the μ opioid receptor are known to the person skilled in the art. The determination is preferably carried out as described in connection with the examples.

The compounds according to the invention preferably have a K_(i) value on the ORL1 receptor of at most 500 nM, more preferably at most 100 nM or at most 50 nM, still more preferably at most 10 nM, most preferably at most 1.0 nM and in particular at most 0.75 nM.

Methods for determination of the K_(i) value on the ORL1 receptor are known to the person skilled in the art. The determination is preferably carried out as described in connection with the examples.

It has been found, surprisingly, that the compounds according to the invention having affinity for the ORL1 and μ plaid receptor have a pharmacological profile which has significant advantages compared with the other opioid receptor ligands:

-   -   1. The compounds according to the invention show an activity in         acute pain models which is sometimes comparable to that of the         usual level 3 opioids. At the same time, however, they are         distinguished by a clearly better tolerability compared with         conventional μ opioids.     -   2. In contrast to the usual level 3 opioids, the compounds         according to the invention show a clearly higher activity in         mono- and polyneuropathy pain models, which is to be attributed         to a synergism of the ORL1 and μ opioid component.     -   3. In contrast to the usual level 3 opioids, the compounds         according to the invention show a substantial, preferably a         complete separation of antiallodynic or antihyperalgesic action         and antinociceptive effect in neuropathic animals.     -   4. In contrast to the usual level 3 opioids, the compounds         according to the invention show a clear intensification of         action against acute pain in animal models for chronic         inflammation pain (inter alia carrageenan- or CFA-induced         hyperalgesia, visceral inflammation pain).     -   5. In contrast to the usual level 3 opioids, side effects         typical of μ opioids (inter alia respiratory depression,         opioid-induced hyperalgesia, physical dependency/withdrawal,         emotional dependency/addiction) are clearly reduced or         preferably are not to be observed with the compounds according         to the invention in the therapeutically active dose range.

On the basis of the reduced μ opioid side effects on the one hand and the increased activity on chronic, preferably neuropathic pain on the other hand, the mixed ORL1/μ agonists are thus distinguished by clearly increased safety margins compared with pure μ opioids. This results in a clearly increased “therapeutic window” in the treatment of states of pain, preferably chronic pain, still more preferably neuropathic pain.

A preferred embodiment of the invention relates to compounds of the general formula (2), i.e. Y₁′, Y₂′, Y₃ and Y₄′ are each —H:

In a preferred embodiment of the compound (2) according to the invention Y₁, Y₂, Y₃ and Y₄ are not —H. In another preferred embodiment of the compound (2) according to the invention three of the radicals Y₁, Y₂, Y₃ and Y₄ are not —H and the remaining radical is —H. In another preferred embodiment two of the radicals Y₁, Y₂, Y₃ and Y₄ are not —H and the remaining two radicals are —H. In a further preferred embodiment of the compound (2) according to the invention one of the radicals Y₁, Y₂, Y₃ and Y₄ is not —H and the remaining radicals are —H.

In a particularly preferred embodiment of the compound (2) according to the invention Y₁, Y₂, Y₃ and Y₄ each represent —H.

Particularly preferred compounds of the general formula (1) or (2) are those wherein

R₀ in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂.

A preferred embodiment of the compound (2) according to the invention relates to compounds of the general formula (2.1):

Particularly preferred compounds of the general formula (2) are those wherein

R₃ represents —C₁₋₈-aliphatic, -aryl, -heteroaryl, —C₁₋₃-aliphatic-aryl, —C₁₋₃-aliphatic-heteroaryl or —C₁₋₃-aliphatic-C₅₋₆-cycloaliphatic; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂;

and

X₁, X₁′, X₂, X₂′, X₃, X₃′ in each case independently of each other represent —H, —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —SR₅, —SO₂R₅, —S(═O)₂OR₅, —ON, —COOR₅, —CONR₅, —NR₆R₇, or —R₀; or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O.

Particularly preferred compounds are those of the general formula (3), i.e. Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ are each —H:

In further embodiments of the compounds of the general formula (3) one of the radicals X₁ and X₁′ represents H and the other represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —Cl, —Br, —CN, —CH₃, —C₂H₅, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂.

Preferred embodiments of the compounds of the general formula (3) have the general formula (3.1):

These embodiments relate to compounds of the general formula (3) in which X₁ and X₁′ are —H.

Particularly preferred compounds of the general formula (3.1) are those wherein

X₂, X₂′, X₃ and X₃′ represent H; or X₂ and X₂′, or X₃ and X₃′ together represent ═O;

R₀ in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂;

R₁ represents CH₃;

R₂ represents —H or —CH₃; or

R₁ and R₂ together form a ring and represent —(CH₂)₃₋₄—; and

R₃ represents —C₁₋₈-aliphatic, -aryl, -heteroaryl, —C₁₋₃-aliphatic-aryl, —C₁₋₃-aliphatic-heteroaryl or —C₁₋₃-aliphatic-C₅₋₆-cycloaliphatic; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂; and

R₄ represents H or —Z—R₁₁,

-   -   wherein     -   Z can be absent or —C(═O)—, —S(═O)— or —S(═O)₂—, and     -   R₁₁ represents —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or         —C₁₋₃-alkyl-C₃₋₆-cycloalkyl, wherein in the C₃₋₆-cycloalkyl         group a ring carbon atom can be replaced by an oxygen atom and         —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl can         be unsubstituted, mono- or polysubstituted with substituents         independently of each other selected from the group consisting         of —F, —Cl, —Br, —I, —CN, —OH, —SH, —O—C₁₋₃-alkyl and         —S—C₁₋₃-alkyl, wherein —C₁₋₃-alkyl can be substituted by one or         more substituents from the group consisting of —F, —Cl, —Br, —I,         —CN, —OH, —OCH₃, —SH and —SCH₃;

Preferred embodiments of the compounds of the general formula (3.1) have the general formula (3.1.1), (3.1.2), (3.1.3), (3.1.4), (3.1.5) or (3.1.6):

A further preferred embodiment relates to compounds of the general formula (4.1), i.e. R₁ and R₂ are in each case —CH₃.

Preferred embodiments of the compounds of the general formula (4.1) have the general formula (4.1.1), (4.1.2), (4.1.3), (4.1.4), (4.1.5) or (4.1.6):

Preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently of each other are chosen from the group consisting of —H, —F, —Cl, —Br, —I, —CN, —NH₂, —NH—C₁₋₆-aliphatic, —NH—C₃₋₆-cycloaliphatic, —NH—C₁₋₆-aliphatic-OH, —N(C₁₋₆-aliphatic)₂, —N(C₃₋₈-cycloaliphatic)₂, —N(C₁₋₆-aliphatic-OH)₂, —NO₂, —NH—C₁₋₆-aliphatic-C₃₋₆-cycloaliphatic, —NH—C₁₋₆-aliphatic-aryl, —NH—C₁₋₆-aliphatic-heteroaryl, —NH-aryl, —NH-heteroaryl, —SH, —S—C₃₋₈-cycloaliphatic, —S—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —S—C₁₋₆-aliphatic-aryl, —S—C₁₋₆-aliphatic-heteroaryl, —S-aryl, —S-heteroaryl, —OH, —O—C₁₋₆-aliphatic, —O—C₃₋₆-cycloaliphatic, —O—C₁₋₆-aliphatic-OH, —O—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —O—C₁₋₆-aliphatic-aryl, —O—C₁₋₆-aliphatic-heteroaryl, —O-aryl, —O— heteroaryl, —O—C(═O)C₁₋₆-cycloaliphatic, —O—C(═O)C₁₋₆-aliphatic-OH, —O—C(═O)C₁₋₆-aliphatic-C₃₋₆-cycloaliphatic, —O—C(═O)C₁₋₆-aliphatic-aryl, —O—C(═O)C₁₋₆-aliphatic-heteroaryl, —O—C(═O)aryl, —O—C(═O)heteroaryl, —C₁₋₆-aliphatic, —C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-heteroaryl, -aryl, -heteroaryl, —C(═O)C₁₋₆-aliphatic, —C(═O)C₃₋₆-cycloaliphatic, —C(═O)C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C(═O)C₁₋₆-aliphatic-aryl, —C(═O)C₁₋₆-aliphatic-heteroaryl, —C(═O)aryl, —C(═O)heteroaryl, —CO₂H, —CO₂—C₁₋₆-aliphatic, —CO₂—C₃₋₈-cycloaliphatic, —CO₂—C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —CO₂—C₁₋₆-aliphatic-aryl, —CO₂—C₁₋₆-aliphatic-heteroaryl, —CO₂-aryl, —CO₂-heteroaryl; or Y₁ and Y₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ together represent ═O.

More preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently of each other are chosen from the group consisting of —H, —F, —Cl, —Br, —I, —CN, —C₁₋₆-aliphatic, —C₁₋₆-aliphatic-NHC₁₋₆-aliphatic, —C₁₋₆-aliphatic-N(C₁₋₈-aliphatic)₂, —C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-heteroaryl, —S—C₁₋₈-aliphatic, —S-aryl, -aryl or -heteroaryl.

Particularly preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently of each other are chosen from the group consisting of —H, —F, —Cl, —C₁₋₆-alkyl, —C₂₋₆-alkenyl, —C₁₋₆-alkyl-NH—C₁₋₆-alkyl, —C₁₋₆-alkyl-N(C₁₋₆-alkyl)₂, -aryl, —C₁₋₆-alkyl-aryl, —S—C₁₋₆-alkyl and —S-aryl.

In a preferred embodiment at least one of the radicals Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ is not —H and the remaining radicals represent —H.

Particularly preferably, Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ each represent —H.

Preferably, X₁, X₁′, X₂, X₂′, X₃ and X₃′ in each case independently of each other represent —H, —F, —Cl, —Br, —I, —NO₂, —NR₆R₇, —C₁₋₆-aliphatic, —C₃₋₈-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-heteroaryl or —C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O; or X₁ and X₂, or X₂ and X₃ together represent —(CH₂)₂₋₆; or X₁ and X₁′ together represent a C₃-C₆-cycloaliphatic, preferably a C₃₋₆-cycloalkyl.

Preferred compounds are in particular also those in which X₁, X₁′, X₂, X₂′, X₃ and X₃′ in each case independently of each other represent —H, —C₁₋₅-aliphatic, -aryl or -aryl linked via a —C₁₋₃-aliphatic group (bridge); or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O.

Particularly preferably, X₁, X₁′, X₂, X₂′, X₃ and X₃′ in each case independently of each other represent —H, —CH₃, -phenyl or -benzyl, in particular —H, or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O.

Very particularly preferably, X₁, X₁′, X₂, X₂′, X₃ and X₃′ represent H; or X₂ and X₂′, or X₃ and X₃′ together represent ═O.

In a preferred embodiment X₂ and X₂′ together represent ═O, and X₁, X₁′, X₃ and X₃′ represent —H.

In another preferred embodiment X₃ and X₃′ together represent ═O, and X₁, X₁′, X₂ and X₂′ represent —H.

In a further preferred embodiment X₁, X₁′, X₂, X₂′, X₃ and X₃′ represent H.

R₀ preferably in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or —C₁₋₈-aliphatic-heteroaryl. In this context —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl or —C₁₋₈-aliphatic-heteroaryl means that the radicals —C₃₋₁₂-cycloaliphatic, -aryl or -heteroaryl are in each case bonded via a divalent —C₁₋₈-aliphatic-bridge. Preferred examples for —C₁₋₈-aliphatic-aryl are —CH₂—C₆H₅, —CH═CH—C₆H₅ and —CH₂CH₂—C₆H₅. A preferred example for —C₁₋₈-aliphatic-heteroaryl is —CH₂-pyridyl. A preferred example for —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic is —CH₂-cyclopentyl.

Preferably, R₁ and R₂ independently of each other represent —H; —C₁₋₆-aliphatic; —C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic or —C₁₋₆-aliphatic-heteroaryl; or the radicals R₁ and R₂ together form a ring and denote —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₈CH₂CH₂— or —(CH₂)₃₋₆—.

More preferably, R₁ and R₂ independently of each other represent —H; —C₁₋₅-aliphatic; or the radicals R₁ and R₂ together form a ring and denote —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₈—CH₂CH₂— or —(CH₂)₃₋₆—, wherein R₈ preferably denotes —H or —C₁₋₅-aliphatic.

Particularly preferred compounds are those wherein R₁ and R₂ independently of each other represent —CH₃ or —H, wherein R₁ and R₂ do not simultaneously denote —H; or R₁ and R₂ form a ring and denote —(CH₂)₃₋₄—.

Very particularly preferred compounds are those wherein R₁ and R₂ represent —CH₃.

Preferably, R₃ represents —C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic, -aryl, -heteroaryl; or represents -aryl, -heteroaryl or —C₃₋₈-cycloaliphatic in each case bonded via a —C₁₋₃-aliphatic group.

Preferably, R₃ represents —C₁₋₅-aliphatic; in each case saturated or unsaturated, unsubstituted or mono- or polysubstituted by —OH, —OCH₃ or —OC₂H₅; -aryl, -heteroaryl; in each case unsubstituted or mono- or polysubstituted by —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂; or represents —C₅₋₆-cycloaliphatic bonded via a —C₁₋₃-aliphatic group.

Most preferably, R₃ represents -aryl, -heteroaryl; in each case unsubstituted or mono- or polysubstituted by —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂; or represents a —C₅₋₆-cycloaliphatic bonded via a —C₁₋₃-aliphatic group.

Particularly preferably, R₃ represents -vinyl, -ethyl, -allyl, -propyl, -butyl, -pentyl, -hexyl, -heptyl, -cyclopentyl, -cyclohexyl, -phenyl, -benzyl, -naphthyl, -anthracenyl, -thiophenyl (-thienyl), -benzothiophenyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyridyl, -pyrimidyl or -pyrazinyl, in each case unsubstituted or mono- or polysubstituted; or —C₅₋₆-cycloaliphatic, -phenyl, -naphthyl, -anthracenyl, -thiophenyl, -benzothiophenyl, pyridyl, -furyl, -benzofuranyl, -benzodioxolanyl, -indolyl, -indanyl, -benzodioxanyl, -pyrrolyl, -pyrimidyl, -triazolyl or -pyrazinyl bonded via a saturated, unbranched —C₁₋₃-aliphatic group and in each case unsubstituted or mono- or polysubstituted.

Still more preferably, R₃ represents -propyl, -butyl, -pentyl, -hexyl, -phenyl, -phenethyl, -thiophenyl (-thienyl), -pyridyl, -triazolyl, -benzothiophenyl or -benzyl, in each case substituted or unsubstituted, particularly preferably -propyl, -3-methoxypropyl, -butyl, -pentyl, -hexyl, -phenyl, -3-methylphenyl, -3-fluorophenyl, -benzo[1,3]-dioxolyl, -thienyl, -5-methylthiophen-2-yl, -benzothiophenyl, -4-chlorobenzyl, -benzyl, -3-chlorobenzyl, -4-methylbenzyl, -2-chlorobenzyl, -4-fluorobenzyl, -3-methylbenzyl, -2-methylbenzyl, -3-fluorobenzyl, -2-fluorobenzyl, -1-methyl-1,2,4-triazolyl or -phenethyl.

Most preferably, R₃ represents -phenyl, -benzyl, -phenethyl, in each case unsubstituted or mono- or polysubstituted on the ring; —C₁₋₅-aliphatic, —C₄₋₆-cycloaliphatic, -pyridyl, -thienyl, -thiazolyl, -imidazolyl, -1,2,4-triazolyl or -benzimidazolyl, unsubstituted or mono- or polysubstituted.

Particularly preferably, R₃ represents -phenyl, -benzyl, -phenethyl, -thienyl, -pyridyl, -thiazolyl, -imidazolyl, -1,2,4-triazolyl, -benzimidazolyl or -benzyl, unsubstituted or mono- or polysubstituted by —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂; -ethyl, -n-propyl, -2-propyl, -allyl, -n-butyl, -iso-butyl, -sec-butyl, -tert-butyl, -n-pentyl, -iso-pentyl, -neo-pentyl, -n-hexyl, -cyclopentyl or -cyclohexyl, in each case unsubstituted or mono- or polysubstituted by —OH, —OCH₃ or —OC₂H₅.

Particularly preferably, R₃ represents -phenyl or -thienyl, in each case unsubstituted or monosubstituted by —F, —Cl, —CH₃; -ethyl, -n-propyl, -n-butyl, -vinyl, or -allyl, unsubstituted or mono- or polysubstituted by —OCH₃, —OH or —OC₂H₅, in particular by —OCH₃ or —OC₂H₅.

In further preferred embodiments, R₃ represents a radical selected from the group consisting of phenyl, benzyl and 2-thienyl, in each case unsubstituted or mono- or polysubstituted by substituents independently of each other selected from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂.

Preferably, R₄ represents H or —Z—R₁₁,

wherein

-   -   Z can be absent or —C(═O)—, and     -   R₁₁ represents —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl, or         C₁₋₃-alkyl-C₃₋₆-cycloalkyl, wherein in the C₃₋₆-cycloalkyl group         a ring carbon atom can be replaced by an oxygen atom and         —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl can         be unsubstituted, mono- or polysubstituted, by substituents         independently of each other selected from the group consisting         of —F, —Cl, —Br, —I, —CN, —OH, —SH, —O—C₁₋₃-alkyl, and         —S—C₁₋₃-alkyl, wherein —C₁₋₃-alkyl can be substituted by one or         more substituents independently of each other selected from the         group consisting of —F, —Cl, —Br, —CN, —OH, —OCH₃, —SH and         —SCH₃.

Preferably, in the radical R₁₁ the —C₃₋₆-cycloalkyl groups and oxygen-containing derivatives thereof are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl(tetrahydrofuranyl) and oxanyl(tetrahydropyranyl).

In further preferred embodiments R₄ represents H, CH₃, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, iso-butyl, t-butyl, n-pentyl, s-pentyl, iso-pentyl,

Preferably, R₅ represents —H, —C₁₋₅-aliphatic, —C₃₋₈-cycloaliphatic, -aryl, or -heteroaryl; or represents an -aryl, —C₃₋₈-cycloaliphatic or -heteroaryl in each case bonded via a —C₁₋₃-aliphatic group.

Preferably, R₆ and R₇ independently of each other represent —H, —C₁₋₅-aliphatic, —C₃₋₈-cycloaliphatic, -aryl, or -heteroaryl, or represent an -aryl, —C₃₋₈-cycloaliphatic or -heteroaryl in each case bonded via a —C₁₋₃-aliphatic group; or R₆ and R₇ together form —CH₂CH₂OCH₂CH₂—, —CH₂CH₂N—R₁₀CH₂CH₂— or —(CH₂)₃₋₆—. Particularly preferably, R₆ and R₇ independently of each other represent —H, —C₁₋₅-aliphatic; or R₆ and R₇ together form —CH₂CH₂OCH₂CH₂—, —CH₂CH₂N—R₁₀CH₂CH₂— or —(CH₂)₃₋₆—.

Preferably, R₈ represents —H, —C₁₋₅-aliphatic, —C₃₋₈-cycloaliphatic, -aryl, or -heteroaryl, —C₁₋₆-aliphatic-aryl, —C₁₋₆-aliphatic-C₃₋₈-cycloaliphatic, —C₁₋₆-aliphatic-heteroaryl, —C(═O)aryl, —C(═O)heteroaryl, or —C(═O)—C₁₋₆-aliphatic.

Particularly preferably, R₁₀ represents —H or —C₁₋₅-aliphatic.

For the purpose of the description, hydrocarbon radicals are divided into aliphatic hydrocarbon radicals on the one hand and aromatic hydrocarbon radicals on the other hand.

Aliphatic hydrocarbon radicals are in their turn divided into non-cyclic aliphatic hydrocarbon radicals on the one hand (=“aliphatic”) and cyclic aliphatic hydrocarbon radicals, i.e. alicylic hydrocarbon radicals, on the other hand (=“cycloaliphatic”). Cycloaliphatics can be monocyclic or multicyclic. Alicyclic hydrocarbon radicals (“cycloaliphatic”) include both pure aliphatic carbocycles and aliphatic heterocycles, i.e.—if not expressly specified—“cycloaliphatic” includes pure aliphatic carbocycles (e.g. cyclohexyl), pure aliphatic heterocycles (e.g. piperidyl or piperazyl) and non-aromatic, multicyclic, optionally mixed systems (e.g. decalinyl, decahydroquinolinyl). In other words the term “cycloaliphatic” is understood here as meaning that both cycloalkyls and heterocycloalkyls as well as unsaturated—but not aromatic—derivatives fall under this term. The term “C₃₋₈-cycloaliphatic” thus includes, inter alia, both 3- to 8-membered cycloalkyls, such as e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and 3- to 8-membered non-aromatic heterocycles in which one or more carbon atoms or —(CH₂)— groups are replaced by a hetero atom (e.g. tetrahydrofuranyl, tetrahydropyranyl, piperidyl or piperazyl etc.).

Aromatic hydrocarbon radicals are in their turn divided into carbocyclic aromatic hydrocarbons on the one hand (=“aryl”) and heterocyclic aromatic hydrocarbons on the other hand (=“heteroaryl”).

The assignment of multicyclic, at least partially aromatic systems preferably depends on whether at least one aromatic ring of the multicyclic system contains at least one hetero atom (conventionally N, O or S) in the ring. If at least one such hetero atom is present in this ring, the system is preferably a “heteroaryl” (even if a further carbocyclic aromatic or non-aromatic ring with or without a hetero atom is present optionally as an additionally present ring of the multicyclic system); if such a hetero atom is present in none of the optionally several aromatic rings of the multicyclic system, the system is preferably “aryl” (even if a ring hetero atom is present in an optionally additionally present non-aromatic ring of the multicyclic system).

Within the cyclic substituents, the following priority of assignment accordingly preferably applies: heteroaryl>aryl>cycloaliphatic.

For the purpose of the description, monovalent and polyvalent, e.g. divalent hydrocarbon radicals are not differentiated with respect to terminology, i.e. “C₁₋₃-aliphatic” includes, depending on the sense, e.g. both —C₁₋₃-alkyl, —C₁₋₃-alkenyl and —C₁₋₃-alkynyl, and e.g. —C₁₋₃-alkylene-, —C₁₋₃-alkenylene- and —C₁₋₃-alkynylene-.

Preferably, “aliphatic” is in each case is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon radical. If aliphatic is mono- or polysubstituted, the substituents independently of each other are chosen from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)—NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —NHS(═O)₁₋₂R₀, —Si(R₀)₃, —PO(OR₀)₂. “Aliphatic” thus includes acyclic saturated or unsaturated hydrocarbon radicals, which can be branched or straight-chain, i.e. alkanyls, alkenyls and alkynyls. In this context alkenyls have at least one C═C double bond and alkynyls have at least one C≡C triple bond. Preferred unsubstituted monovalent aliphatics include —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —CH₂CH₂CH₂—CH₂CH₃ and —CH₂CH₂—CH₂CH₂CH₂CH₃; but also —CH═CH₂, —C≡CH, —CH₂CH═CH₂, —CH═CHCH₃, —CH₂C≡CH, —C≡CCH₃ and —CH═CHCH═CH₂. Preferred unsubstituted divalent aliphatics include —CH₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH(CH₃)—CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)—CH₂—, —CH₂CH₂CH(CH₃)—, —CH—(CH₂CH₃)CH₂— and —CH₂CH₂—CH₂CH₂—; but also —CH═CH—, —CH₂CH═CH—, —CH═CHCH₂—, —CH₂C≡C— and —C≡CCH₂—. Preferred substituted monovalent aliphatics include —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃, —CH₂OH, —CH₂CH₂OH, —CH₂CHOHCH₃, —CH₂OCH₃ and CH₂CH₂OCH₃. Preferred substituted divalent aliphatics include —CF₂—, —CF₂CF₂—, —CH₂CHOH—, —CHOHCH₂— and —CH₂CHOHCH₂—.

Methyl, ethyl, n-propyl and n-butyl are particularly preferred aliphatics.

Preferably, cycloaliphatic is in each case a saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic (i.e. non-aromatic), mono- or multicyclic hydrocarbon radical. The number of ring carbon atoms is preferably in the stated range (i.e. a “C₃₋₈-” cycloaliphatic preferably has 3, 4, 5, 6, 7 or 8 ring carbon atoms). For the purpose of the description, “C₃₋₈-cycloaliphatic” is preferably a cyclic hydrocarbon having 3, 4, 5, 6, 7 or 8 ring carbon atoms, saturated or unsaturated, but not aromatic, one or two carbon atoms independently of each other optionally being replaced by a hetero atom S, N or O. If cycloalkyl is mono- or polysubstituted, the substituents independently of each other are chosen from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, NHS(═O)₁₂R₀, —Si(R₀)₃, —PO(OR₀)₂. C₃₋₈-Cycloaliphatic is advantageously chosen from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.

Cyclopentyl and cyclohexyl are particularly preferred C₃₋₈-cycloaliphatics.

Preferably, in connection with “aliphatic” or “cycloaliphatic”, “mono- or polysubstituted” is understood as meaning substitution once or several times, e.g. once, twice, three times or four times, of one or more hydrogen atoms by —F, —Cl, —Br, —OH, —OC₁₋₆-alkyl, —OC(═O)C₁₋₆-alkyl, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compounds wherein “aliphatic substituted” or “cycloaliphatic substituted” means aliphatic or cycloaliphatic substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂ are preferred. Particularly preferred substituents are —F, —Cl, —OH, —SH, —NH₂ and —C(═O)OH.

Polysubstituted radicals are to be understood as meaning those radicals which are polysubstituted, e.g. di- or trisubstituted, either on different or on the same atoms, for example trisubstituted on the same C atom, as in the case of —CF₃ or —CH₂CF₃, or at different places, as in the case of —CH(OH)—CH═CH—CHCl₂. Polysubstitution can be with the same or with various substituents. A substituent can optionally also be substituted in its turn; thus -Oaliphatic, inter alia, also includes —OCH₂CH₂O—CH₂CH₂—OH. It is preferable for aliphatic or cycloaliphatic to be substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂. It is very particularly preferable for aliphatic or cycloaliphatic to be substituted by —OH, —OCH₃ or —OC₂H₅.

Preferably, “aryl” in each case independently represents a carbocyclic ring system having at least one aromatic ring, but without hetero atoms in this ring, wherein the aryl radicals can optionally be fused with further saturated, (partially) unsaturated or aromatic ring systems and each aryl radical can be unsubstituted or mono- or polysubstituted, wherein the substituents on aryl can be identical or different and can be in any desired and possible position of the aryl. Preferred aryls are phenyl, naphthyl, anthracenyl, phenanthrenyl, fluoranthenyl, fluorenyl, indanyl and tetralinyl. Phenyl and naphthyl are particularly preferred. If aryl is mono- or polysubstituted, the substituents on aryl can be identical or different and can be in any desired and possible position of the aryl, and are independently of each other chosen from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)—NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)—NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂. Preferred substituted aryls are 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl and 3,4-dimethylphenyl.

Preferably, heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the hetero atoms are identical or different and are nitrogen, oxygen or sulfur and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of substitution on the heterocycle the substituents can be identical or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system. Preferably, “heteroaryl” is chosen from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzooxadiazolyl, benzothiazolyl, benzooxazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, where bonding can be via any desired and possible ring member of the heteroaryl radical. If heteroaryl is mono- or polysubstituted, the substituents on heteroaryl can be identical or different and can be in any desired and possible position of the heteroaryl, and are independently of each other chosen from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)OH, —C(═O)OR₀, —C(═O)—NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —O(CH₂)₁₋₂O—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)—N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NH—C(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂; wherein N ring atoms optionally present can in each case be oxidised (N-oxide).

With respect to “aryl” or “heteroaryl”, “mono- or polysubstituted” is understood as meaning substitution once or several times, e.g. twice, three times, four times or five times, of one or more hydrogen atoms of the ring system.

The substituents on aryl and heteroaryl are particularly preferably in each case independently of each other chosen from —F, —Cl, —Br, —I, —CN, —CHO, —CO₂H, —NH₂, —NO₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —SH, —SR₀, —OH, —OR₀, —C(═O)R₀, —CO₂R₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —S(═O)₁₋₂R₀, —S(═O)₂NH₂, —SO₃H, ═O or —R₀. Preferred substituents are —F, —Cl, —Br, —I, —OH, —OC₁₋₆-alkyl, —O—C(═O)—C₁₋₆-alkyl, —SH, —NH₂, —NHC₁₋₆-alkyl, —N(C₁₋₆-alkyl)₂, —C(═O)OC₁₋₆-alkyl or —C(═O)OH. Compounds wherein “aryl substituted” or “heteroaryl substituted” means aryl or heteroaryl substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂ are preferred. Particularly preferred substituents are —F, —Cl, —CH₃, —OH, —SH, —NH₂ and —C(═O)OH.

The compounds according to the invention can be in the form of an individual stereoisomer or mixture thereof, the free compounds and/or their physiologically acceptable salts and/or solvates.

With respect to the Spiro ring, the compounds according to the invention are isomers in which the substitution pattern on the Spiro cyclohexane ring system can also be designated cis/trans, Z/E or syn/anti. “cis-trans isomers” are a sub-group of stereoisomers (configuration isomers).

The cis-trans isomers of the compound of the general formula (1) according to the invention have the general formula (1a) or (1b):

The assignment of the two stereoisomers (1a) and (1b) according to the substitution pattern as the cis or trans isomer is known to the person skilled in the art.

In a preferred embodiment the diastereomer excess of the cis isomer is at least 50% de, more preferably at least 75% de, still more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de. In another preferred embodiment, the diastereomer excess of the trans isomer is at least 50% de, more preferably at least 75% de, still more preferably at least 90% de, most preferably at least 95% de and in particular at least 99% de.

Suitable methods for separation of the isomers (diastereomers) are known to the person skilled in the art. Examples which may be mentioned are column chromatography, preparative HPLC and crystallization methods.

A person skilled in the art moreover recognises that the compounds according to the invention can be chiral or achiral, depending on the substitution pattern.

If the compounds according to the invention are chiral, they are preferably in the form of the racemate or in a concentrated form of one enantiomer. In a preferred embodiment the enantiomer excess (ee) of the S enantiomer is at least 50% ee, more preferably at least 75% ee, still more preferably at least 90% ee, most preferably at least 95% ee and in particular at least 99% ee. In another preferred embodiment the enantiomer excess (ee) of the R enantiomer is at least 50% ee, more preferably at least 75% ee, still more preferably at least 90% ee, most preferably at least 95% ee and in particular at least 99% de.

Suitable methods for separation of the enantiomers are known to the person skilled in the art. Examples which may be mentioned are preparative HPLC on chiral stationary phases and conversion into diastereomeric intermediates. The conversion into diastereomeric intermediates can be carried out, for example, as salt formation with the aid of chiral, enantiomerically pure acids. After the separation of the diastereomers formed in this way, the salt can then be converted back into the free base or another salt.

If not expressly specified, any reference to the compounds according to the invention includes all the isomers (e.g. stereoisomers, diastereomers, enantiomers) in any desired mixing ratio.

If not expressly specified, any reference to the compounds according to the invention includes the free compounds (i.e. the forms which are not in the form of a salt) and all physiologically acceptable salts.

For the purpose of the description, physiologically acceptable salts of the compounds according to the invention are in the form of salts with anions or acids of the particular compound with inorganic or organic acids which are physiologically acceptable—in particular when used in humans and/or mammals.

Examples of physiologically acceptable salts of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The hydrochloride, the citrate and the hemicitrate are particularly preferred.

Physiologically acceptable salts with cations or bases are salts of the particular compound—as the anion with at least one, preferably inorganic cation—which are physiologically acceptable—in particular when used in humans and/or mammals. The salts of alkali metals and alkaline earth metals but also ammonium salts are particularly preferred, but in particular (mono)- or (di)sodium, (mono)- or (di)potassium, magnesium or calcium salts.

The compounds according to the invention are defined by substituents, for example by R₁, R₂ and R₃ (substituents of the 1st generation), which in their turn are optionally substituted (substituents of the 2nd generation). Depending on the definition, these substituents of the substituents can in their turn be substituted again (substituents of the 3rd generation). For example, if Y₁=—R₀, wherein R₀=—C₁₋₈-aliphatic (substituent of the 1st generation), —C₁₋₈-aliphatic can in its turn be substituted, e.g. by —OR₀, wherein R₀=-aryl (substituent of the 2nd generation). The functional group —C₁₋₈-aliphatic-Oaryl results from this. -Aryl can then in its turn be substituted again, e.g. by —Cl (substituent of the 3rd generation). The functional group —C₁₋₈-aliphatic-Oaryl-Cl overall then results from this.

In a preferred embodiment, however, the substituents of the 3rd generation cannot be substituted again, i.e. there are then no substituents of the 4th generation.

In another preferred embodiment, however, the substituents of the 2nd generation cannot be substituted again, i.e. there are then already no substituents of the 3rd generation. In other words, in this embodiment the functional groups for R₀ to R₁₀ can in each case be optionally substituted, but the particular substituents cannot then in their turn be substituted again.

In another preferred embodiment the substituents of the 1st generation already cannot be substituted again, i.e. there are then neither substituents of the 2nd nor substituents of the 3rd generation. In other words, in this embodiment the functional groups for R₀ to R₁₀ in each case cannot be substituted.

Preferred compounds are those wherein “aliphatic substituted” or “cycloaliphatic substituted” means aliphatic or cycloaliphatic substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂; and “aryl substituted” or “heteroaryl substituted” means aryl or heteroaryl substituted by —F, —Cl, —Br, —I, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, —OH, —OCH₃, —OC₂H₅ or —N(CH₃)₂ in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or of an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.

Very particularly preferred compounds are those according to the general formula (3)

in which X₁ and X₁ represent H and the radicals R₁, R₂, R₃, R₄, X₂/X₂′ and X₃/X₃′ have the following meaning:

Example R₁ R₂ R₃ X₂/X₂′ X₃/X₃′ R₄ 1; 2 CH₃ CH₃ Benzyl H/H ═O H 3; 4 CH₃ CH₃ Benzyl H/H H/H H 5; 6 CH₃ CH₃ Benzyl H/H H/H CH₃ 7; 8 CH₃ CH₃ Benzyl H/H H/H Acetyl  9 CH₃ CH₃ Benzyl H/H H/H n-Butyl 10; 11 CH₃ CH₃ Benzyl H/H H/H

 12 CH₃ CH₃ Benzyl H/H H/H

 13 CH₃ CH₃ Phenyl H/H ═O H 14; 15 CH₃ CH₃ Phenyl ═O H/H H  16 CH₃ CH₃ n-Butyl H/H ═O H  17 CH₃ CH₃ 2-Thienyl H/H ═O H 18; 25 CH₃ CH₃ 2-Thienyl H/H H/H H  19 CH₃ CH₃ 2-Thienyl H/H H/H CH₃ 20a/b CH₃ CH₃ 2-Thienyl H/H H/H

 21 CH₃ CH₃ 2-Thienyl H/H H/H n-Butyl  22 CH₃ CH₃ 2-Thienyl H/H H/H

24a/b CH₃ CH₃ 2-Thienyl ═O H/H H  27 CH₃ CH₃ Benzyl H/H H/H n-Butyl 28; 29 CH₃ CH₃ Phenyl H/H H/H

 30 CH₃ CH₃

H/H ═O H  31 CH₃ CH₃

H/H H/H H  32 CH₃ CH₃

H/H H/H

 33 CH₃ CH₃ 2-Thienyl ═O H/H n-Butyl  34 CH₃ CH₃ 2-Thienyl ═O H/H CH₃  35 CH₃ CH₃

H/H H/H n-Butyl  36 CH₃ CH₃

H/H H/H

 37 CH₃ CH₃

H/H H/H

 38 CH₃ CH₃

H/H H/H

 39 CH₃ CH₃

H/H H/H

 40 CH₃ CH₃

H/H H/H

 41 CH₃ CH₃

H/H H/H

 42 CH₃ CH₃ 2-Thienyl H/H H/H

 43 CH₃ CH₃ 2-Thienyl H/H H/H

 44 CH₃ CH₃ 2-Thienyl H/H H/H

 45 CH₃ CH₃ 2-Thienyl H/H H/H

 46 CH₃ CH₃ 2-Thienyl H/H H/H

 47 CH₃ CH₃ 2-Thienyl H/H H/H

 48 CH₃ CH₃ 2-Thienyl H/H H/H

 49 CH₃ CH₃ 2-Thienyl H/H H/H

 50 CH₃ CH₃ 2-Thienyl H/H H/H

 51 CH₃ CH₃ 2-Thienyl H/H H/H

 52 CH₃ CH₃ 2-Thienyl H/H H/H

 53 CH₃ CH₃ 2-Thienyl H/H H/H

 54 CH₃ CH₃ 2-Thienyl H/H H/H

 55 CH₃ CH₃ 2-Thienyl H/H H/H

 56 CH₃ CH₃ 2-Thienyl H/H H/H

 57 CH₃ CH₃ 2-Thienyl H/H H/H

 58 CH₃ CH₃ 2-Thienyl H/H H/H

 59 CH₃ CH₃ 2-Thienyl H/H H/H

 60 CH₃ CH₃ 2-Thienyl H/H H/H

 61 CH₃ CH₃ 2-Thienyl H/H H/H

 62 CH₃ CH₃ 2-Thienyl H/H H/H

 63 CH₃ CH₃ 2-Thienyl H/H H/H

 64 CH₃ CH₃ 2-Thienyl H/H H/H

 65 CH₃ CH₃ 2-Thienyl H/H H/H

 66 CH₃ CH₃ 2-Thienyl H/H H/H

 67 CH₃ CH₃ 2-Thienyl H/H H/H

 68 CH₃ CH₃ 2-Thienyl H/H H/H

 69 CH₃ CH₃ 2-Thienyl H/H H/H

 70 CH₃ CH₃ 2-Thienyl H/H H/H

 71 CH₃ CH₃ Phenyl H/H H/H H  72 CH₃ CH₃ Phenyl H/H H/H

 73 CH₃ CH₃ Phenyl H/H H/H Acetyl  74 CH₃ CH₃ Phenyl H/H H/H n-Butyl  75 CH₃ CH₃ Phenyl H/H H/H

 76 CH₃ CH₃ Phenyl H/H H/H

 77 CH₃ CH₃ Phenyl H/H H/H

 78 CH₃ CH₃ Phenyl H/H H/H

 79 CH₃ CH₃ Phenyl H/H H/H

 80 CH₃ CH₃ Phenyl H/H H/H

 81 CH₃ CH₃ Phenyl H/H H/H

 82 CH₃ CH₃ Phenyl H/H H/H

 83 CH₃ CH₃ Phenyl H/H H/H

 84 CH₃ CH₃ Phenyl H/H H/H

 85 CH₃ CH₃ Phenyl H/H H/H

 86 CH₃ CH₃ Phenyl H/H H/H

 87 CH₃ CH₃ Phenyl H/H H/H

 88 CH₃ CH₃

H/H H/H

 89 CH₃ CH₃

H/H H/H n-Butyl  90 CH₃ CH₃

H/H H/H

 91 CH₃ CH₃

H/H H/H n-Butyl  92 CH₃ CH₃

H/H H/H H  93 CH₃ CH₃

H/H H/H

 94 CH₃ CH₃

H/H H/H n-Butyl  95 CH₃ CH₃

H/H H/H

 96 CH₃ CH₃

H/H H/H n-Butyl  97 CH₃ CH₃

H/H H/H

 98 CH₃ CH₃

H/H H/H n-Butyl  99 CH₃ CH₃

H/H H/H

100 CH₃ CH₃

H/H H/H

101 CH₃ CH₃

H/H H/H

102 CH₃ CH₃

H/H H/H

103 CH₃ CH₃

H/H H/H

104 CH₃ CH₃

H/H H/H

105 CH₃ CH₃

H/H H/H

106; 107 CH₃ CH₃

H/H H/H n-Butyl 108; 109 —CH₂CH₂CH₂— 2-Thienyl H/H H/H

110; 111 —CH₂CH₂CH₂— Phenyl H/H H/H

112; 113 —CH₂CH₂CH₂— Phenyl H/H H/H n-Butyl 114 CH₃ CH₃ 2-Thienyl H/H ═O CH₃ 115 CH₃ CH₃ 2-Thienyl H/H ═O n-Butyl 116 CH₃ CH₃ 2-Thienyl H/H ═O

117 CH₃ CH₃

H/H ═O H 118; 119 CH₃ CH₃ Benzyl H/H ═O CH₃ 120; 121 CH₃ CH₃ Benzyl H/H ═O n-Butyl 122; 123 CH₃ CH₃ Benzyl H/H ═O

124 CH₃ CH₃ 2-Thienyl ═O H/H CH₃ 125 CH₃ CH₃ 2-Thienyl ═O H/H n-Butyl 126; 127 CH₃ CH₃ 2-Thienyl ═O H/H

128; 129 CH₃ CH₃ 2-Thienyl ═O H/H

130; 131 CH₃ CH₃ 2-Thienyl ═O H/H

132; 133 CH₃ CH₃ 2-Thienyl ═O H/H

134; 135 CH₃ CH₃ 2-Thienyl ═O H/H

136; 137 CH₃ CH₃ 2-Thienyl ═O H/H

138; 139 CH₃ CH₃ 2-Thienyl ═O H/H

140; 141 CH₃ CH₃ 2-Thienyl ═O H/H

142; 143 CH₃ CH₃ 2-Thienyl ═O H/H

144; 145 CH₃ CH₃ 2-Thienyl ═O H/H

146; 147 CH₃ CH₃ 2-Thienyl ═O H/H

148; 149 CH₃ CH₃ 2-Thienyl ═O H/H

150; 151 CH₃ CH₃ 2-Thienyl ═O H/H

152; 153 CH₃ CH₃

═O H/H H 154; 155 CH₃ CH₃

═O H/H CH₃ 156; 157 CH₃ CH₃

═O H/H n-Butyl 158; 159 CH₃ CH₃

═O H/H

160 CH₃ CH₃

═O H/H

161 CH₃ CH₃

═O H/H

162 CH₃ CH₃ Phenyl ═O H/H CH₃ 163; 164 CH₃ CH₃ Phenyl ═O H/H n-Butyl 165; 166 CH₃ CH₃ Phenyl ═O H/H

167; 168 CH₃ CH₃ Phenyl ═O H/H

169; 170 CH₃ CH₃ Phenyl ═O H/H

171; 172 CH₃ CH₃ Phenyl ═O H/H

173; 174 CH₃ CH₃ Phenyl ═O H/H

175; 176 CH₃ CH₃ Phenyl ═O H/H

177; 178 CH₃ CH₃ Phenyl ═O H/H

179; 180 CH₃ CH₃ Phenyl ═O H/H

181 CH₃ CH₃ Phenyl ═O H/H

182; 183 CH₃ CH₃ Phenyl ═O H/H

184; 185 CH₃ CH₃ Phenyl ═O H/H

186; 187 CH₃ CH₃ Phenyl ═O H/H

188 CH₃ CH₃ Phenyl H/H H/H

189 CH₃ CH₃ Phenyl H/H H/H

190 CH₃ CH₃ Phenyl H/H H/H

191 CH₃ CH₃ Phenyl H/H H/H

192 CH₃ CH₃ Phenyl H/H H/H

193 CH₃ CH₃ Phenyl H/H H/H

194 CH₃ CH₃ Phenyl H/H H/H

195 CH₃ CH₃ Phenyl H/H H/H

196 CH₃ CH₃ Phenyl H/H H/H

197 CH₃ CH₃ Phenyl H/H H/H

198 CH₃ CH₃ Phenyl H/H H/H

199 CH₃ CH₃ Phenyl H/H H/H

200 CH₃ CH₃ Phenyl H/H H/H

201 CH₃ CH₃ Phenyl H/H H/H

202 CH₃ CH₃ Phenyl H/H H/H

203 CH₃ CH₃ Phenyl H/H H/H

204 CH₃ CH₃ Phenyl H/H H/H

205 CH₃ CH₃ Phenyl H/H H/H

206 CH₃ CH₃ Phenyl H/H H/H

207 CH₃ CH₃ 2-Thienyl H/H H/H

208 CH₃ CH₃ 2-Thienyl H/H H/H

209 CH₃ CH₃ 2-Thienyl H/H H/H

210 CH₃ CH₃ 2-Thienyl H/H H/H

211 CH₃ CH₃ 2-Thienyl H/H H/H

212 CH₃ CH₃ 2-Thienyl H/H H/H

213 CH₃ CH₃ 2-Thienyl H/H H/H

214 CH₃ CH₃

H/H H/H

215; 216 CH₃ CH₃ 2-Thienyl ═O H/H

217; 218 CH₃ CH₃ 2-Thienyl ═O H/H

219; 220 CH₃ CH₃ 2-Thienyl ═O H/H

221; 222 CH₃ CH₃ 2-Thienyl ═O H/H

223 CH₃ CH₃ 2-Thienyl H/H H/H

224; 225 CH₃ CH₃ 2-Thienyl ═O H/H

226 CH₃ CH₃ 2-Thienyl H/H H/H

227 CH₃ CH₃ 2-Thienyl H/H H/H

228 CH₃ CH₃ Phenyl H/H H/H

229 CH₃ CH₃ Phenyl H/H H/H

230; 231 CH₃ CH₃ Phenyl ═O H/H

232 CH₃ CH₃ Phenyl H/H H/H

233 CH₃ CH₃ 2-Thienyl H/H H/H

234 CH₃ CH₃

═O H/H

235 CH₃ CH₃ 2-Thienyl H/H H/H

236 CH₃ CH₃

═O H/H

237 CH₃ CH₃ Phenyl H/H H/H

238 CH₃ CH₃ 2-Thienyl H/H H/H

239 CH₃ CH₃ 2-Thienyl H/H H/H

240 CH₃ CH₃ 2-Thienyl ═O H/H

241; 242 CH₃ CH₃ 2-Thienyl ═O H/H

243 CH₃ CH₃

═O H/H

244 CH₃ CH₃

═O H/H

245 CH₃ CH₃

═O H/H

246 CH₃ CH₃

═O H/H

247 CH₃ CH₃

H/H H/H

248 CH₃ CH₃ 2-Thienyl H/H H/H

249 CH₃ CH₃ Phenyl H/H H/H

250 CH₃ CH₃ 2-Thienyl ═O H/H

251; 252 CH₃ CH₃ Phenyl ═O H/H

253 CH₃ CH₃ 2-Thienyl H/H H/H

254; 255 CH₃ CH₃ Phenyl ═O H/H

256 CH₃ CH₃

═O H/H

257 CH₃ CH₃

H/H H/H

258 CH₃ CH₃

H/H H/H

259 CH₃ CH₃

H/H H/H

260; 261 CH₃ CH₃ Phenyl ═O H/H

262; 263 CH₃ CH₃ Phenyl ═O H/H

264 CH₃ CH₃ Phenyl ═O H/H

265 CH₃ CH₃

H/H H/H

266 CH₃ CH₃

H/H H/H

267 CH₃ CH₃

H/H H/H

268 CH₃ CH₃

H/H H/H

269; 270 CH₃ CH₃ Phenyl ═O H/H

271 CH₃ CH₃ Phenyl ═O H/H

272 CH₃ CH₃ Phenyl H/H H/H

273 CH₃ CH₃

H/H H/H

274 CH₃ CH₃

═O H/H

275 CH₃ H Phenyl ═O H/H

276 CH₃ CH₃

═O H/H

277 CH₃ CH₃

═O H/H

278 CH₃ CH₃

═O H/H

279; 280 CH₃ CH₃ 2-Thienyl ═O H/H

281 CH₃ CH₃

═O H/H n-Butyl 282 CH₃ CH₃

═O H/H CH₃ 283 CH₃ CH₃ Phenyl H/H H/H

284 CH₃ CH₃ Phenyl H/H H/H

285 CH₃ CH₃ Phenyl H/H H/H

286 CH₃ CH₃

═O H/H

287 CH₃ CH₃

═O H/H

288; 289 CH₃ CH₃ 2-Thienyl ═O H/H

290 CH₃ H 2-Thienyl ═O H/H

291 CH₃ CH₃

H/H H/H

292 CH₃ CH₃

H/H H/H

293; 294 CH₃ CH₃

═O H/H

295 CH₃ CH₃ 2-Thienyl H/H H/H

296 CH₃ CH₃ 2-Thienyl H/H H/H

297 CH₃ CH₃

H/H H/H

298 CH₃ CH₃

H/H H/H

299 CH₃ CH₃ 2-Thienyl H/H H/H

300 CH₃ CH₃ Phenyl H/H H/H

301 CH₃ CH₃

H/H H/H

302 CH₃ CH₃

H/H H/H

303 CH₃ CH₃ Phenyl H/H H/H

304 CH₃ CH₃ 2-Thienyl H/H H/H

305 CH₃ CH₃ Phenyl H/H H/H

306 CH₃ CH₃ 2-Thienyl H/H H/H

307; 308 CH₃ H 2-Thienyl ═O H/H

309 CH₃ CH₃ 2-Thienyl H/H H/H

310 CH₃ CH₃ Phenyl ═O H/H

311 CH₃ CH₃ 2-Thienyl ═O H/H

312 CH₃ CH₃ Phenyl ═O H/H

313 CH₃ CH₃ 2-Thienyl ═O H/H

314 CH₃ CH₃ 2-Thienyl H/H H/H

315 CH₃ CH₃ 2-Thienyl H/H H/H

316 CH₃ H 2-Thienyl ═O H/H

317 CH₃ CH₃ 2-Thienyl ═O H/H

318 CH₃ CH₃ 2-Thienyl ═O H/H

319 CH₃ CH₃ Phenyl ═O H/H

320 CH₃ CH₃ Phenyl H/H H/H

321 CH₃ CH₃ 2-Thienyl ═O H/H

322 CH₃ CH₃ Phenyl ═O H/H

323 CH₃ CH₃ Phenyl ═O H/H

324 CH₃ CH₃ Phenyl ═O H/H

325 CH₃ CH₃ Phenyl ═O H/H

326 CH₃ CH₃ Phenyl ═O H/H

327 CH₃ CH₃ 2-Thienyl H/H H/H

328 CH₃ CH₃ Phenyl H/H H/H

329 CH₃ CH₃ Phenyl H/H H/H

330 CH₃ H Phenyl ═O H/H

331 CH₃ H Phenyl ═O H/H

332 CH₃ CH₃ 2-Thienyl ═O H/H

333 CH₃ CH₃ 2-Thienyl H/H H/H

334 CH₃ CH₃ 2-Thienyl ═O H/H

335 CH₃ CH₃ Phenyl ═O H/H

336 CH₃ CH₃

═O H/H

337 CH₃ CH₃

═O H/H

338 CH₃ CH₃ Phenyl H/H H/H

339 CH₃ CH₃ 2-Thienyl H/H H/H

340 CH₃ CH₃ Phenyl ═O H/H

341 CH₃ H 2-Thienyl ═O H/H

342 CH₃ CH₃ Phenyl H/H H/H

343 CH₃ CH₃ Phenyl H/H H/H

344 CH₃ CH₃ 2-Thienyl ═O H/H

345 CH₃ CH₃ Phenyl H/H H/H

346 CH₃ H 2-Thienyl H/H H/H

347 CH₃ CH₃ 2-Thienyl ═O H/H

348 CH₃ CH₃ Phenyl ═O H/H

349 CH₃ CH₃ Phenyl ═O H/H

350 CH₃ CH₃ Phenyl H/H H/H

351 CH₃ CH₃ 2-Thienyl H/H H/H

352 CH₃ CH₃ Phenyl H/H H/H

353 CH₃ CH₃ 2-Thienyl ═O H/H

354 CH₃ CH₃ Phenyl H/H H/H

355 CH₃ CH₃ 2-Thienyl H/H H/H

356 CH₃ CH₃ 2-Thienyl H/H H/H

357 CH₃ CH₃ Phenyl ═O H/H

358 CH₃ CH₃ 2-Thienyl H/H H/H

359 CH₃ CH₃ Phenyl H/H H/H

360 CH₃ CH₃ 2-Thienyl H/H H/H

361 CH₃ CH₃ 2-Thienyl H/H H/H

362 CH₃ CH₃ Phenyl H/H H/H

363 CH₃ CH₃ 2-Thienyl H/H H/H

364 CH₃ CH₃ n-Butyl H/H H/H

365 CH₃ CH₃ Phenyl H/H H/H

366 CH₃ CH₃ Phenyl H/H H/H

367 CH₃ CH₃ n-Butyl H/H H/H

368 CH₃ CH₃ n-Butyl H/H H/H

369 CH₃ CH₃ Phenyl H/H H/H

370 CH₃ CH₃ 2-Thienyl ═O H/H

371 CH₃ CH₃ Phenyl H/H H/H

372 CH₃ CH₃ 2-Thienyl H/H H/H

373 CH₃ CH₃ 2-Thienyl H/H H/H

374 CH₃ CH₃ Phenyl H/H H/H

375 CH₃ CH₃ n-Butyl H/H H/H

376 CH₃ CH₃ Phenyl ═O H/H

377 CH₃ CH₃ 2-Thienyl ═O H/H

378 CH₃ CH₃ Phenyl ═O H/H

379 CH₃ CH₃ Phenyl H/H H/H

380 CH₃ CH₃ Phenyl H/H H/H

381 CH₃ CH₃ Phenyl H/H H/H

382 CH₃ CH₃ 2-Thienyl H/H H/H

383 CH₃ CH₃ 2-Thienyl H/H H/H

384 CH₃ CH₃ 2-Thienyl H/H H/H

385 CH₃ CH₃ 2-Thienyl H/H H/H

386 CH₃ CH₃ 2-Thienyl ═O H/H

387 CH₃ CH₃ Phenyl ═O H/H

388 CH₃ CH₃ n-Butyl H/H H/H

389 CH₃ CH₃ n-Butyl H/H H/H

390 CH₃ CH₃ Phenyl H/H H/H

391 CH₃ CH₃

H/H H/H

392 CH₃ CH₃

H/H H/H

393 CH₃ CH₃

H/H H/H

394 CH₃ CH₃ Phenyl H/H H/H

395 CH₃ CH₃ 2-Thienyl H/H H/H

396 CH₃ CH₃

H/H H/H

397 CH₃ CH₃

H/H H/H

398 CH₃ CH₃

H/H H/H

399; 400 CH₃ CH₃ n-Butyl ═O H/H

401; 402 CH₃ CH₃ n-Butyl ═O H/H

403; 404 CH₃ CH₃ n-Butyl ═O H/H

405 CH₃ CH₃ Phenyl H/H H/H

406 CH₃ CH₃ n-Butyl ═O H/H

407 CH₃ CH₃

H/H H/H

408 CH₃ CH₃ Phenyl H/H H/H

409; 410 CH₃ CH₃ n-Butyl ═O H/H

411 CH₃ CH₃

H/H H/H

412 CH₃ CH₃ 2-Thienyl H/H H/H

413 CH₃ CH₃ n-Butyl ═O H/H

414 CH₃ CH₃ Phenyl H/H H/H

415 CH₃ CH₃ 2-Thienyl H/H H/H

416 CH₃ CH₃ 2-Thienyl H/H H/H

417 CH₃ CH₃

═O H/H

418 CH₃ CH₃

H/H H/H

419 CH₃ H 2-Thienyl H/H H/H

420 CH₃ H Phenyl H/H H/H

421 CH₃ CH₃

═O H/H

422 CH₃ H Phenyl H/H H/H

423 CH₃ H 2-Thienyl H/H H/H

424 CH₃ CH₃

H/H H/H H 425 CH₃ CH₃

H/H H/H H 426 CH₃ CH₃

H/H H/H H 427; 428 —CH₂CH₂CH₂— 2-Thienyl H/H H/H H 429; 430 —CH₂CH₂CH₂— Phenyl H/H H/H H 431 CH₃ CH₃ Phenyl ═O H/H H 432; 433 CH₃ CH₃ n-Butyl ═O H/H H

where these compounds can be in the form of an individual stereoisomer or mixture thereof, the free compounds and/or their physiologically acceptable salts and/or solvates.

The compounds according to the invention act, for example, on the ORL1 receptor relevant in connection with various diseases, so that they are suitable as a pharmaceutical active compound in a medicament.

The invention therefore also provides medicaments which contain at least one compound according to the invention and optionally suitable additives and/or auxiliary substances and/or optionally further active compounds.

The medicaments according to the invention optionally contain, in addition to at least one compound according to the invention, suitable additives and/or auxiliary substances, that is to say also carrier materials, fillers, solvents, diluents, dyestuffs and/or binders, and can be administered as liquid medicament forms in the form of injection solutions, drops or juices, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters/spray-on plasters or aerosols. The choice of auxiliary substances etc. and the amounts thereof to be employed depend on whether the medicament is to be administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example on the skin, the mucous membranes or into the eyes. Formulations in the form of tablets, coated tablets, capsules, granules, drops, juices and syrups are suitable for oral administration, solutions, suspensions, easily reconstitutable dry formulations and sprays are suitable for parenteral, topical and inhalatory administration. Compounds according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote penetration through the skin, are suitable formulations for percutaneous administration. Formulation forms which can be used orally or percutaneously can release the compounds according to the invention in a delayed manner. The compounds according to the invention can also be used in parenteral long-term depot forms, such as e.g. implants or implanted pumps. In principle, other further active compounds known to the person skilled in the art can be added to the medicaments according to the invention.

The amount of active compound to be administered to patients varies as a function of the weight of the patient, of the mode of administration, the indication and the severity of the disease. 0.00005 to 50 mg/kg, preferably 0.001 to 0.5 mg/kg of at least one compound according to the invention are conventionally administered.

For all the above forms of the medicaments according to the invention, it is particularly preferable if the medicament also contains, in addition to at least one compound according to the invention, a further active compound, in particular an opioid, preferably a potent opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.

In a preferred form of the medicament, a compound according to the invention contained therein is in the form of a pure diastereomer and/or enantiomer.

The ORL1 receptor has been identified in particular in the pain event. Compounds according to the invention can accordingly be used for the preparation of a medicament for treatment of pain, in particular acute, visceral, neuropathic or chronic pain.

The invention therefore also provides the use of a compound according to the invention for the preparation of a medicament for treatment of pain, in particular acute, visceral, neuropathic or chronic pain.

The invention also provides the use of a compound according to the invention for the preparation of a medicament for treatment of anxiety states, of stress and syndromes associated with stress, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, impaired hearing, lack of intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for modulation of motor activity, for modulation of neurotransmitter secretion and treatment of neurodegenerative diseases associated therewith, for treatment of withdrawal symptoms and/or for reduction of the addiction potential of opioids.

In this context, in one of the above uses it may be preferable for a compound which is used to be in the form of a pure diastereomer and/or enantiomer, a racemate or a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.

The invention also provides a method for the treatment, in particular in one of the abovementioned indications, of a non-human mammal or a human requiring treatment of pain, in particular chronic pain, by administration of a therapeutically active dose of a compound according to the invention, or of a medicament according to the invention.

The invention also provides a process for the preparation of the compounds according to the invention as described in the following description and examples.

General Synthesis Equations:

In a preferred embodiment the synthesis of the compounds according to the invention follows the following general synthesis equation:

In step 1 compound A (WO2007079930) is converted into the nitrile B under basic conditions (WO2007127763; Reimann, Eberhard et al., Archiv der Pharmazie (Weinheim, Germany) (1988), 321(12), 935-41). The reduction of the nitrile B is carried out e.g. with cobalt boride (WO2007127763), the intermediate C cyclising spontaneously to the lactam D. The lactam D is deprotected under acid conditions (cerium ammonium nitrate/acetonitrile/water (I. Márko et al., Angew. Chem. 1999, 111, 3411-3413; Tetrahedron 2003, 59, 8989-8999), palladium chloride-bis-acetonitrile complex/acetone (B. H. Lipshutz et al., Tetrahedron Lett. 1985, 26, 705-708), sodium iodide/cerium(III) chloride/acetonitrile (E. Marcantoni et al., J. Org. Chem. 1997, 62, 4183-4184) and thiourea/ethanol/water (S. Majumdar, A. Bhattacharjya, J. Org. Chem. 1999, 64, 5682-5685) and then it is converted into the nitrile F in a Strecker reaction (WO2008101660, WO2008009415). The nitrile F reacts in a Bruylants reaction (D. Alberti et al., Bioorg. Med. Chem. Lett. 2006, 16, 4321-4325) with a Grignard reagent to give the compound of the general formula G. The compounds of the general formula G are reduced by methods known from the literature, e.g. with lithium aluminium hydride (Wang, Jun et al., J. Am. Chem. Soc., 131(23), 8066-8076; 2009; Bhandari, Kalpana et al., Chemistry & Industry (London, United Kingdom), (17), 547-8; 1990). By methods known from the literature, the compounds of the general formula H are alkylated (Hutchins, Robert O., Markowitz, Morris J. Org. Chem. 46(17), 3571-4; 1981; Setaki, Despina et al., Bioorg. Chem., 34(5), 248-273; 2006; Stamatiou, G. et al.; Bioorg. & Med. Chem. Lett. 11(16), 2137-2142; 2001), arylated (WO2007070826, U.S. Pat. No. 7,157,456, WO2002085838) and acylated (WO2008034731, WO2008036755, US20070117824, WO2007030061) on the nitrogen. Alternatively, the compound G can also first be alkylated or arylated and thereafter reduced. A polar and a non-polar diastereomer of the general formula G, but preferably the polar diastereomer G, are formed by this synthesis route.

In another preferred embodiment the synthesis of the compounds according to the invention follows the following general synthesis equation:

In step 1 compound A (WO2007079930) is converted into the nitro compound J under basic conditions and then reduced (G. H. Posner, D. R. Crouch, Tetrahedron 1990, 46, 7509-7530; R. J. Flintoft et al., Tetrahedron Lett. 1999, 44, 4485-4488; E. A. Krafft et al., Synthesis 2005, 3245-3252). Further reaction of the compound D is carried out as described in equation 1.

In another preferred embodiment the synthesis of the compounds according to the invention follows the following general synthesis equation:

In step 1 ketones of the general formula K (synthesised analogously to WO2006/031610 and U.S. Pat. No. 6,573,386) are converted into nitriles of the general formula L with TosMIC (Van Leusen, Daan et al., Organic Reactions (Hoboken, N.J., United States), 57, 2001). The nitrile L is converted into the imido-ester M in a Pinner reaction (Whitlock, Gavin A. et al., Bioorg. & Med. Chem. Lett. 18(9), 2930-2934, 2008; Geffken, Detlef et al., Archiv der Pharmazie (Weinheim, Germany), 321(1), 45-9; 1988) and then hydrolysed (US2002/58687). The ester N is converted into the nitrile O under basic conditions, like the ester A in equation 1. The nitrile O is reduced under conditions known from the literature and cyclised to the lactam G (WO2007127763). A polar and a non-polar diastereomer of the general formula G are formed by this synthesis route. Further reaction of compound G is carried out as described in equation 1.

In another preferred embodiment the synthesis of the compounds according to the invention follows the following general synthesis equation:

In step 1 ketones of the general formula K (synthesised analogously to WO2006/031610 and U.S. Pat. No. 6,573,386) are converted into enol triflates (P) (WO2009111056). The aminocarbonylation with ethanolamine proceeds under extremely mild conditions (O. Lagerlund et al., Tetrahedron 2009, 65, 7646-7652; A. I. Meyers et al., Tetrahedron Lett. 1991, 33, 1181-1184). The alcohol Q is converted into a bromine derivative of the general formula R under conditions known from the literature (Van der Mey, Margaretha et al., J. Med. Chem. 45(12), 2520-2525; 2002). An exo-trig cyclisation between a primary radical and an α,β-unsaturated carboxylic acid derivative is then carried out to give the compound G (T. J. Murray et al. Tetrahedron 1995, 51, 635-640). A polar and a non-polar diastereomer of the general formula G are formed by this synthesis route. Further reaction of the compound G is carried out as described in equation 1.

In another preferred embodiment the synthesis of the compounds according to the invention follows the following general synthesis equation:

In step 1 ketones of the general formula K (synthesised analogously to WO2006/031610 and U.S. Pat. No. 6,573,386) are converted into the compounds S in a Homer olefination known from the literature (Wadsworth, W. S., Jr. Et al., Organic Syntheses, 45, 1965). The compounds of the general formula S are reacted with nitromethane in a Michael addition to give the compound T (U.S. Pat. No. 5,091,567; WO2008/129007; J. S. Bryans et al., J. Med. Chem. 1998, 41, 1838-1845). The nitro compound T is reduced under conditions known from the literature and cyclised in situ to give the lactam U (G. H. Posner, D. R. Crouch, Tetrahedron 1990, 46, 7509-7530; R. J. Flintoft et al., Tetrahedron Lett. 1999, 44, 4485-4488; E. A. Krafft et al., Synthesis 2005, 3245-3252). By reduction of U the target compounds of the general formula H are obtained (Wang, Jun et al., J. Am, Chem. Soc., 131(23), 8066-8076; 2009; Bhandari, Kalpana et al., Chemistry & Industry (London, United Kingdom), (17), 547-8; 1990). A polar and a non-polar diastereomer of the general formula U are formed by this synthesis route. By methods known from the literature, the compounds of the general formula H are alkylated (Hutchins, Robert O., Markowitz, Morris J. Org. Chem. 46(17), 3571-4; 1981; Setaki, Despina et al., Bioorg. Chem., 34(5), 248-273; 2006; Stamatiou, G. et al.; Bioorg, & Med. Chem. Lett. 11(16), 2137-2142; 2001), arylated (WO2007070826, U.S. Pat. No. 7,157,456, WO2002085838) and acylated (WO2008034731, WO2008036755, US20070117824, WO2007030061) on the nitrogen. Alternatively, the compound U can also first be alkylated or arylated and thereafter reduced.

With respect to further details of the synthesis of the compounds according to the invention, in particular with respect to the synthesis of suitable educt units, reference is furthermore made to the full scope of WO2004/043967, WO2005/063769, WO2005/066183, WO2006/018184, WO2006/108565, WO2007/124903, WO2008/004915 and WO2008/009416. A person skilled in the art recognises that suitable educt units for the synthesis of the compounds according to the invention can be prepared analogously to the synthesis equations and embodiment examples disclosed in these publications.

EXAMPLES

The following examples serve to illustrate the invention in more detail, but are not to be interpreted as limiting.

The yields of the compounds prepared are not optimized. All the temperatures are uncorrected. The term “ether” means diethyl ether, “EA” ethyl acetate and “MC” methylene chloride. The term “equivalent” means equivalent substance amount, “m.p.” melting point or melting range, “decomp.” decomposition, “RT” room temperature, “abs.” absolute (anhydrous), “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol. %” percent by volume, “wt. %” percent by weight, and “M” is a concentration stated in mol/l.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was employed as the stationary phase for the column chromatography. The thin layer chromatography investigations were carried out with HPTLC precoated plates, silica gel 60 F 254 from E. Merck, Darmstadt. The mixing ratios of mobile phases for chromatography investigations are always stated in volume/volume.

Synthesis Instructions Example No. 1 Step 1: 8-Cyanomethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester

A 2.5 M solution of n-buyllithium in n-hexane (22 ml, 55 mmol) was added dropwise to a solution of diisopropylamine (5.56 g, 55 mmol) in anhydrous tetrahydrofuran (80 ml) under argon at −78° C. and the mixture was than stirred for 15 min at 0° C. A solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (10.7 g, 50 mmol) in tetrahydrofuran (15 ml) was added dropwise to this lemon-yellow solution at −78° C. in the course of 20 min. The dark yellow mixture was stirred for 1.5 h at −78° C. and a solution of bromoacetonitrile (7.16 g, 3.98 ml, 60 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)pyrimidone (DMPU, 3.20 g, 3.0 ml, 25 mmol) in tetrahydrofuran (15 ml) was then added dropwise. Thereafter, the orange-coloured solution was warmed slowly to room temperature and stirred overnight. 0.5 N hydrochloric acid (38 ml) was added to the now red-brown solution and the phases were separated. The aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (2×100 ml) and with saturated sodium chloride solution (4×100 ml), dried with sodium sulfate and concentrated i. vac. The crude product (12.1 g) was purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/cyclohexane (1:2).

Yield: 6.50 g (51%), yellowish oil.

¹H-NMR (CDCl₃): 1.29 (t, 3H, J=7.1 Hz); 1.62-1.76 (m, 6H); 2.17-2.29 (m, 2H); 2.57 (s, 2H): 3.93 (t, 4H, J=22 Hz); 4.23 (q, 2H, J=7.1 Hz).

Step 2: 1,4-Dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one

Sodium borohydride (4.84 g, 128 mmol) was added in portions to a raspberry-coloured mixture of 8-cyanomethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (6.50 g, 25.6 mmol) and anhydrous cobalt(II) chloride (1.66 g, 12.8 mmol) in tetrahydrofuran (100 ml) and water (50 ml) under argon at 0° C. and the mixture was then stirred overnight at room temperature. During this operation the solution became black in colour. Since the reaction was not yet complete, cobalt(II) chloride (830 mg, 6.4 mmol) and sodium borohydride (2.42 g, 64 mmol) were again added and the mixture was stirred for a further 24 h. 25% strength aqueous ammonia solution (5 ml) was added to the reaction mixture and the mixture was filtered. The residue on the filter was washed with tetrahydrofuran/water (2:1). The filtrate was concentrated i. vac. and the aqueous solution was extracted with methylene chloride (3×50 ml). The combined organic extracts were dried with sodium sulfate and concentrated i. vac.

Yield: 4.64 g (86%), white solid which still contained approx. 30% of educt.

Step 3: 2-Azaspiro[4.5]decane-1,8-dione

p-toluenesulfonic acid (5.00 g, 26.3 mmol) was added to a solution of 1,4-dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one (4.64 g, 21.9 mmol) in methanol (75 ml) and water (25 ml) and the mixture was stirred for 24 h at room temperature and 24 h at 50° C. The reaction mixture was then rendered alkaline with 5 N sodium hydroxide solution and concentrated. The residue was diluted with water (50 ml) and the mixture was extracted with methylene chloride (6×30 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (2.09 g) was purified by flash chromatography (200 g, 20×5.7 cm) with ethyl acetate/methylene chloride (4:1) and ethyl acetate/methylene chloride/methanol (3:1:1). The mixed fractions (850 mg) were purified again by flash chromatography (100 g, 20×4.0 cm) with tert-butyl methyl ether/methanol (14:1).

Yield: 1.20 g (33%), white solid

Melting point: 128-130° C.

¹H-NMR (CDCl₃): 1.73-1.89 (m, 2H); 2.08-2.21 (m, 4H); 2.33 (ddd, 2H, J=5.8, 10.2 and 15.0 Hz); 2.70 (td, 2H, J=6.3 and 14.8 Hz); 3.41 (dt, 2H, J=0.8 and 7.1 Hz); 3.72 (s, 1H).

Step 4: Dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile

4 N hydrochloric acid (2.15 ml, 8.56 mmol) and 2-azaspiro[4.5]decane-1,8-dione (1.20 g, 7.17 mmol) in methanol (16 ml) were added to a 40% strength aqueous dimethylamine solution (3.6 ml, 28.7 mmol), cooled to 0° C., and methanol (1.6 ml). Potassium cyanide (931 mg, 14.3 mmol) was added to this mixture and the mixture was stirred over the weekend at room temperature. After addition of water (30 ml) the solution was extracted with diethyl ether and methylene chloride (3×30 ml of each). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 1.40 g (88%), white solid

¹H-NMR (CDCl₃): 1.35-1.67 (m, 3H); 1.76-2.09 (m, 5H); 2.18-2.31 (m, 2H); 2.33 and 2.35 (2s, 6H); 3.28-3.35 (m, 2H); 6.50 and 6.60 (2s, 1H). This is a diastereoisomer mixture in the ratio of approx. 2:1.

Step 5: 8-Benzyl-8-(dimethyl-amino)-3-azaspiro[4.5]decan-4-one (Example no. 1, polar diastereomer, Example no. 2, non-polar diastereomer)

A solution of dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (1.40 g, 6.3 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise to a 2 M solution of benzylmagnesium chloride in tetrahydrofuran (9.5 ml, 19 mmol) at 0° C. under argon and thereafter the mixture was stirred at room temperature overnight. 20% strength ammonium chloride solution (25 ml) was then added to the reaction solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (2.00 g) was purified by flash chromatography (100 g, 20×4.0 cm) with methylene chloride/methanol (48:1) and 0.25% ammonia (25% in water). The mixed fractions (560 mg) were purified again by flash chromatography (38 g, 20×2.5 cm) with methylene chloride/isopropanol (95:5) and 1% ammonia (25% in water).

Example No. 11 Polar Diastereoisomer

Yield: 511 mg (28%), colourless oil which also contains approx. 20% of the non-polar diastereoisomer.

¹H-NMR (CDCl₃): 1.53-1.63 (m, 4H); 1.67-1.75 (m, 2H); 1.85-1.92 (m, 2H); 1.95 (t, 2H, J 6.8 Hz); 2.28 (s, 6H); 2.77 (s, 2H); 3.21-3.26 (m, 2H); 5.71 (br s, 1H); 7.13-7.26 (m, 5H).

¹³C-NMR (CDCl₃): 28.2; 29.0; 35.3; 36.7; 37.4; 38.6; 41.5; 57.6; 125.7; 127.7; 130.8; 139.2; 182.6.

LC-MS: m/z: [M+H]⁺=287.3, R_(t)=1.0 min.

Example No. 2 Non-Polar Diastereoisomer

Yield: 970 mg (54%), white solid

Melting point: 202-204° C.

¹H-NMR (CDCl₃): 1.05-1.19 (m, 4H); 1.67-1.80 (m, 4H); 2.00-2.14 (m, 2H); 2.30 (s, 6H); 2.62 (s, 2H); 3.15 (t, 2H, J=7.2 Hz); 5.90 (br s, 1H); 7.00-7.13 (m, 2H); 7.15-7.28 (m, 3H).

¹³C-NMR (CDCl₃): 26.9; 28.6; 31.6; 37.0; 38.8; 43.6; 57.1; 125.6; 127.7; 130.6; 139.3; 183.3.

LC-MS: m/z: [M+H]⁺=287.3, R_(t)=2.3 min.

Example No. 3 (8-Benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 3, polar diastereomer)

A solution of 8-benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one (polar diastereomer) (663 mg, 2.3 mmol) in anhydrous tetrahydrofuran (35 ml) was added to a suspension of lithium aluminium hydride (436 mg, 11.5 mmol) in anhydrous tetrahydrofuran (20 ml), while cooling with ice, and the mixture was then stirred overnight at 60° C. Water (300 μl), 1 N sodium hydroxide solution (1 ml) and again water (1 ml) were added to the mixture, while cooling with ice, and the mixture was stirred for 1 h at room temperature. The suspension was filtered through sea sand and the residue was washed with tetrahydrofuran. The filtrate was dried with sodium sulfate and concentrated i. vac.

Example No. 3 Polar Diastereoisomer

Yield: 588 mg (94%), colourless oil

A portion of the crude product (165 mg) was purified by flash chromatography (5 g, 15×0.9 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in water), as a result of which the test substance (130 mg) was obtained.

¹H-NMR (CDCl₃): 1.07-1.22 (m, 4H); 1.48 (t, 2H, J=7.2 Hz); 1.62-1.75 (m, 4H); 2.30 (s, 6H); 2.41 (s, 2H); 2.60 (s, 2H); 2.80 (br s, 1H); 2.85 (t, 2H, J=7.2 Hz); 7.08-7.11 (m, 2H); 7.14-7.26 (m, 3H).

¹³C-NMR (CDCl₃): 30.0; 31.3; 36.7; 37.1; 41.1; 42.2; 45.5; 55.9; 57.6; 125.6; 127.7; 130.6; 139.3.

LC-MS: m/z: [M+H]⁺=273.4, R_(t)=0.2 min.

Example No. 4 (8-Benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 4, non-polar diastereomer)

A solution of 8-benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one (non-polar diastereomer) (700 mg, 2.44 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a suspension of lithium aluminium hydride (463 mg, 12.2 mmol) in anhydrous tetrahydrofuran (20 ml), while cooling with ice, and the mixture was then stirred overnight at 60° C. Water (300 μl), 1 N sodium hydroxide solution (1 ml) and again water (1 ml) were added to the mixture, while cooling with ice, and the mixture was stirred for 1 h at room temperature. The suspension was filtered through sea sand and the residue was washed with tetrahydrofuran. The filtrate was dried with sodium sulfate and concentrated i. vac.

Example No. 4 Non-Polar Diastereoisomer

Yield: 640 mg (96%), colourless oil

A portion of the crude product (154 mg) was purified by flash chromatography (5 g, 15×0.9 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in water), as a result of which the test substance (117 mg) was obtained.

¹H-NMR (CDCl₃): 1.09-1.27 (m, 6H); 1.62-1.71 (m, 4H); 2.23 (br s, 1H); 2.29 (s, 6H); 2.58 (s, 2H); 2.61 (s, 2H); 2.82 (t, 2H, J=7.1 Hz); 7.09-7.26 (m, 5H).

¹³C-NMR (CDCl₃): 29.8; 31.3; 36.0; 36.7; 37.1; 42.4; 46.6; 57.6; 61.3; 125.5; 127.6; 130.6; 139.4.

LC-MS: m/z: [M+H]⁺=273.4, R_(t)=0.3 min.

Example No. 5 (8-Benzyl-3-methyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 5, polar diastereomer)

37% strength formalin solution (1.30 ml), glacial acetic acid (650 μl) and sodium cyanoborohydride (205 mg, 3.2 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (polar diastereomer) (207 mg, 0.76 mmol) in methanol (6.5 ml) and the mixture was stirred for 16 h at room temperature. After addition of saturated sodium bicarbonate solution (20 ml) the mixture was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (220 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in water).

Example No. 5 Polar Diastereoisomer

Yield: 160 mg (73%), white solid

Melting point: 89-91° C.

¹H-NMR (CDCl₃): 1.07-1.17 (m, 2H); 1.26-1.33 (m, 2H); 1.56 (t, 2H, J=6.9 Hz); 1.62-1.72 (m, 4H); 2.07 (s, 2H); 2.21 (s, 3H); 2.29 (s, 6H); 2.43 (t, 2H, J=6.9 Hz); 2.61 (s, 2H); 7.09-7.13 (m, 2H); 7.15-7.27 (m, 3H).

¹³C-NMR (CDCl₃): 30.1; 33.3; 36.8; 37.2; 40.8; 41.7; 42.7; 55.6; 57.5; 66.7; 125.6; 127.7; 130.7; 139.5.

LC-MS: m/z: [M+H]⁺=287.3, R_(t)=0.2 min.

Example No. 6 (8-Benzyl-3-methyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 6, non-polar diastereomer)

37% strength formalin solution (1 ml), glacial acetic acid (500 μl) and sodium cyanoborohydride (138 mg, 2.2 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (non-polar diastereomer) (150 mg, 0.55 mmol) in methanol (5 ml) and the mixture was stirred for 16 h at room temperature. After addition of saturated sodium bicarbonate solution (20 ml) the mixture was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (199 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in water).

Example No. 6 Non-Polar Diastereoisomer

Yield: 110 mg (70%), white solid

Melting point: 57-58° C.

¹H-NMR (CDCl₃): 1.18-1.30 (m, 4H); 1.37 (t, 2H, J=6.9 Hz); 1.64-1.77 (m, 4H); 2.28 (s, 3H); 2.31 (s, 2H); 2.33 (s, 6H); 2.45 (t, 2H, J=6.9 Hz); 2.65 (s, 2H); 7.14-7.31 (m, 5H). The signal at 4.76 ppm (s) belongs to an unknown impurity.

¹³C-NMR (CDCl₃): 29.4: 32.8; 36.0; 36.8; 37.1; 41.5; 42.7; 56.4; 57.5; 71.2; 74.8; 125.5; 127.7, 130.7; 139.4. One of the signals between 56.0 and 75.0 belongs to an unknown impurity.

LC-MS: m/z: [M+H]⁺=287.4, R_(t)=0.2 min.

Example No. 7 1-[8-Benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-3-yl]-ethanone (Example no. 7, polar diastereomer)

Triethylamine (203 mg, 279 μl, 2.01 mmol) and acetic anhydride (137 mg, 126 μl, 1.34 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (polar diastereomer) (183 mg, 0.67 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 3 h at room temperature. After addition of methylene chloride (30 ml) the solution was washed with 25% strength saturated potassium carbonate solution (10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (220 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia.

Example No. 7 Polar Diastereoisomer

Yield: 138 mg (65%), colourless oil

¹H-NMR (CDCl₃): 1.05-1.25 (m, 4H); 1.59-1.77 (m, 6H); 1.88 and 1.98 (2 s, 3H); 2.28 and 2.30 (2 s, 6H); 2.60 and 2.63 (2 s, 2H); 2.92 and 3.05 (2 s, 2H); 3.37-3.45 (m, 2H); 7.04-7.29 (m, 5H).

¹³C-NMR (CDCl₃): 22.1; 22.4; 29.7; 29.74; 29.9; 36.8; 36.9; 37.0; 37.1; 38.2; 39.8; 40.2; 42.1; 43.7; 45.7; 54.0; 55.8; 57.6; 57.62; 125.8; 126.0; 127.8; 128.0; 130.5; 130.6; 138.8; 139.1; 169.2; 169.4.

The sometimes doubled signal sets are based on hindered rotation.

LC-MS: m/z: [M+H]⁺=315.3, R_(t)=2.3 min.

Example No. 8 1-[8-Benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-3-yl]-ethanone (Example no. 8, non-polar diastereomer)

Triethylamine (188 mg, 258 μl, 1.86 mmol) and acetic anhydride (126 mg, 116 μl, 1.24 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (non-polar diastereomer) (169 mg, 0.62 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 3 h at room temperature. After addition of methylene chloride (40 ml) the solution was washed with 25% strength saturated potassium carbonate solution (10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (203 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia.

Example No. 8 Non-Polar Diastereoisomer

Yield: 146 mg (75%), colourless oil

¹H-NMR (CDCl₃): 1.11-1.26 (m, 4H); 1.54 and 1.52 (2 t, 2H, J=7.2 Hz); 1.63-1.77 (m, 4H); 1.97 and 1.98 (2 s, 3H); 2.28 and 2.95 (2 s, 6H); 2.63 (s, 2H); 3.14 and 3.19 (2 s, 2H); 3.34 and 3.38 (2 t, 2H, J=7.2 Hz); 7.09-7.29 (m, 5H).

¹³C-NMR (CDCl₃): 22.0; 22.4; 29.0; 29.1; 29.54; 29.57; 32.2; 33.6; 36.5; 36.6; 37.0; 40.2; 41.9; 44.3; 46.1; 57.6; 57.62; 58.3; 60.8; 125.6; 125.8; 127.8; 127.9; 130.6; 130.7; 139.0; 139.3; 169.1; 169.2.

The sometimes doubled signal sets are based on hindered rotation.

LC-MS: m/z: [M+H]⁺=315.3, R_(t)=2.5 min.

Example No. 9 (8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 9, non-polar diastereomer)

Sodium cyanoborohydride (177 mg, 2.82 mmol) and butyraldehyde (86 mg, 106 μl, 1.19 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (non-polar diastereomer) (162 mg, 0.59 mmol) in methanol (5 ml) and the mixture was stirred for 30 min at room temperature. Glacial acetic acid (600 μl) was added to the mixture and the mixture was stirred for a further 16 h at room temperature. After addition of saturated sodium bicarbonate solution (20 ml) the mixture was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (202 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia.

Example No. 9 Non-Polar Diastereoisomer

Yield: 150 mg (87° A)), colourless oil

¹H-NMR (CDCl₃): 0.92 (t, 3H, J=7.3 Hz); 1.10-1.20 (m, 2H); 1.26-1.40 (m, 4H); 1.52-1.65 (m, 4H); 1.67-1.82 (m, 4H); 2.28 (s, 6H); 2.62 (s, 2H); 2.70-2.77 (m, 4H); 2.95 (br t, 2H, J=6.5 Hz); 7.07-7.11 (m, 2H); 7.16-7.28 (m, 3H).

¹³C-NMR (CDCl₃): 13.6; 20.2; 28.5; 29.2; 31.4; 33.5; 36.5; 37.0; 41.3; 53.8; 56.3; 57.3; 66.7; 125.8; 127.9; 130.6; 138.8.

LC-MS: m/z: [M+H]⁺=329.4, R_(t)=1.2 min.

Example No. 10 (8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 10, polar diastereomer)

Butyryl chloride (134 mg, 132 μl, 1.26 mmol) was added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (polar diastereomer) (169 mg, 0.62 mmol) and triethylamine (193 mg, 264 μl, 1.9 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with methylene chloride (20 ml) and washed with 25% strength potassium carbonate solution (2×10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (240 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 10 Polar Diastereoisomer

Yield: 159 mg (75%), colourless oil

¹H-NMR (CDCl₃): 0.88 and 0.93 (2 t, 3H, J=7.4 Hz); 1.04-1.23 (m, 4H); 1.53-1.77 (m, 8H); 2.04 and 2.77 (2 t, 2H, J=7.5 Hz); 2.28 and 2.30 (2 s, 6H); 2.60 and 2.63 (2 s, 2H); 2.92 and 3.06 (2 s, 2H); 3.36-3.44 (m, 2H); 7.04-7.29 (m, 5H).

¹³C-NMR (CDCl₃): 13.9; 14.0; 18.3; 18.5; 29.59; 29.6; 29.8; 29.9; 36.4; 36.7; 36.8; 36.84; 37.0; 37.1; 37.9; 39.7; 40.0; 42.0; 43.7; 44.9; 54.0; 54.9; 57.61; 57.64; 125.7; 125.9; 127.8; 128.0; 130.5; 130.6; 138.8; 139.1; 171.9.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=343.4, R_(t)=2.7 min.

Example No. 11 (8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 11, non-polar diastereomer)

Butyryl chloride (134 mg, 132 μl, 1.26 mmol) was added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (non-polar diastereomer) (173 mg, 0.63 mmol) and triethylamine (193 mg, 264 μl, 1.9 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 18 h at room temperature. The reaction mixture was diluted with methylene chloride (20 ml) and washed with 25% strength potassium carbonate solution (2×10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (220 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (300:5) and 1% ammonia (25% in water).

Example No. 11 Non-Polar Diastereoisomer

Yield: 157 mg (73%), white solid

Melting point: 98-105° C.

¹H-NMR (CDCl₃): 0.93 and 0.94 (2 t, 3H, J=7.4 Hz); 1.12-1.26 (m, 4H); 1.41 and 1.50 (2 t, 2H, J=7.1 Hz); 1.59-1.77 (m, 6H); 2.13-2.19 (m, 2H); 2.28 and 2.30 (2 s, 6H); 2.62 (s, 2H); 3.16 and 3.19 (2 s, 2H); 3.33 and 3.38 (2 t, 2H, J=7.1 Hz); 7.09-7.28 (m, 5H).

¹³C-NMR (CDCl₃): 14.0; 14.02; 18.3; 18.4; 29.0; 29.1; 29.5; 29.6; 32.0; 33.6; 36.2; 36.5; 36.6; 36.8; 37.0; 40.0; 41.9; 44.3; 45.3; 57.6; 57.7; 58.4; 60.0; 125.6; 125.7; 127.8; 127.9; 130.6; 130.7; 139.1; 139.3; 171.6; 171.7.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=343.3, R_(t)=2.9 min.

Example No. 12 (8-Benzyl-3-(cyclopentylmethyl)-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 12, non-polar diastereomer)

Cyclopentanecarbaldehyde (125 mg, 136 μl, 1.3 mmol) and glacial acetic acid (500 μl) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (non-polar diastereomer) (202 mg, 0.74 mmol) in methanol (5 ml) and the mixture was stirred for 2 h at room temperature. After addition of sodium cyanoborohydride (200 mg, 3.1 mmol) the mixture was stirred for 24 h at room temperature. The reaction mixture was then diluted with methylene chloride (20 ml), saturated sodium bicarbonate solution (25 ml) was added and the phases were separated. The aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (283 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 12 Non-Polar Diastereoisomer

Yield: 192 mg (73%), colourless oil

¹H-NMR (CDCl₃): 1.11-1.29 (m, 6H); 1.37 (t, 2H, J=6.9 Hz); 1.45-1.80 (m, 10H); 1.98 (td, 1H, J=15.4, 7.8 Hz); 2.29 (s, 6H); 2.39 (d, 2H, J=7.2 Hz); 2.41 (s, 2H); 2.58 (t, 2H, J=6.9 Hz); 2.62 (s, 2H); 7.09-7.25 (m, 5H).

¹³C-NMR (CDCl₃): 25.1; 29.4; 31.5; 32.5; 34.6; 36.7; 37.1; 38.8; 41.0; 54.7; 57.5; 62.5; 68.5; 125.6; 127.7; 130.7; 139.3.

LC-MS: m/z: [M+H]⁺=355.4, R_(t)=2.0 min.

Example No. 13 8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-4-one (Example no. 13, a diastereomer)

A solution of dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (330 mg, 1.49 mmol) in tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (2.4 ml, 4.8 mmol) at 0° C. and under argon and thereafter the mixture was stirred overnight at room temperature. 20% strength ammonium chloride solution (15 ml) was then added to the reaction solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×15 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (520 mg) was purified by flash chromatography (45 g, 23×2.5 cm) with methylene chloride/methanol (95:5) and 0.5% ammonia (33% in H₂O).

Example No. 13 A Diastereomer

Yield: 155 mg (38%), white solid

Melting point: 183-185° C.

¹H-NMR (CDCl₃): 1.30-1.37 (m, 2H); 1.61 (t, 2H, J=13.5 Hz); 1.97 (t, 2H, J=6.9 Hz); 2.05 (s, 6H); 2.21 (dt, 2H, J=3.1 and 13.1 Hz); 2.62 (br d, 2H, J=14.4 Hz); 3.26-3.32 (m, 2H); 6.17 (br s, 1H); 7.21-7.30 (m, 1H); 7.30-7.39 (m, 4H).

¹³C-NMR (CDCl₃): 28.2 (2C); 29.3; 32.8; 37.9 (2C); 38.8 (2C); 43.1; 58.7; 126.5; 126.8 (2C); 127.5 (2C); 139.4; 182.9.

LC-MS: m/z: [M+H]⁺=273.3, R_(t)=1.4 min.

Example No. 14 and Example No. 15 Step 1: (4-Dimethylamino-4-phenylcyclohexylidene)acetic acid ethyl ester

Potassium tert-butylate (1.93 g, 17.3 mmol) was added to a solution of phosphonoacetic acid triethyl ester (3.86 g, 314 ml, 17.3 mmol) in anhydrous N,N-dimethylformamide (20 ml) under argon. The mixture was stirred for 10 min at room temperature and a solution of 4-(dimethylamino)-4-phenylcyclohexanone (2.50 g, 11.5 mmol) in anhydrous N, N-dimethylformamide (40 ml) was then added and thereafter the mixture was stirred for 1 h at room temperature and then poured into ice-water (50 g). The aqueous suspension was extracted with diethyl ether (4×40 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 3.39 g (100%)

¹H-NMR (CDCl₃): 1.26 (t, 3H, J=7.1 Hz); 2.06 (s, 6H); 2.10-2.25 (m, 5H); 2.45 (m, 1H); 2.67 (m, 1H); 3.20 (m, 1H); 4.13 (q, 2H, J=7.1 Hz); 5.60 (s, 1H); 7.26 (m, 1H); 7.31-7.40 (m, 4H).

LC-MS: [M+H]⁺: m/z=288.3, R_(t)=2.7 min.

Step 2: (4-Dimethylamino-2-nitromethyl-4-phenylcyclohexyl)acetic acid ethyl ester

Nitromethane (138 mg, 122 μl, 2.26 mmol) was added to a mixture of (4-dimethylamino-4-phenylcyclohexylidene)acetic acid ethyl ester (500 mg, 1.74 mmol) and tetra-n-butylammonium fluoride trihydrate (602 mg, 1.91 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 6 h at 70° C. The reaction mixture was then concentrated in vacuo and the residue (1.10 g) was purified by flash chromatography (38 g, 20×2.5 cm) with ethyl acetate/methanol (95:5).

Yield: 453 mg (75%), yellowish oil.

¹H-NMR (DMSO-d₆): The spectrum shows all the required signals. This is a diastereoisomer mixture in the ratio of approx. 3:2.

Step 3: 8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one (Example no. 14, polar diastereomer, Example no. 15, non-polar diastereomer)

A solution of (4-dimethylamino-2-nitromethyl-4-phenylcyclohexyl)acetic acid ethyl ester (1.13 g, 3.24 mmol) in ethanol (32 ml) was added to a mixture of iron powder (904 mg, 16.2 mmol), ammonium chloride (4.33 g, 81 mmol) and water (3.3 ml) and the mixture was then stirred for 5 h at 80° C. The mixture was filtered and the residue was washed with ethanol. The filtrate was rendered alkaline with 5% strength sodium bicarbonate solution (1 ml) and then concentrated i. vac. The crude product was purified by flash chromatography (38 g, 20×2.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water). The diastereoisomer mixture isolated was separated by medium pressure chromatography on a PuriFlash cartridge (PF-15SIHP, 40 g) with the above eluent.

Example No. 14 Polar Diastereoisomer

Yield: 330 mg (37%), white solid

Melting point: 210-215° C.

¹H-NMR (CDCl₃): 1.35-1.45 (m, 2H); 1.73-1.82 (m, 2H); 1.86-2.01 (m, 2H); 2.02 (s, 6H); 2.05 (s, 2H); 2.10-2.30 (m, 2H); 3.26 (s, 2H); 6.28 (s, 1H); 7.25-7.30 (m, 3H); 7.35-7.40 (m, 2H).

¹³C-NMR (CDCl₃): 30.2; 32.7; 37.98; 38.0; 39.0; 43.3; 52.8; 53.4; 60.1; 126.7; 127.4; 127.7; 136.0; 177.4.

LC-MS: m/z: [M+H]⁺=273.3, R_(t)=1.3 min.

Example No. 15 Non-Polar Diastereoisomer

Yield: 215 mg (24%), white solid

Melting point: 218-223° C.

¹H-NMR (CDCl₃): 1.35-1.45 (m, 2H); 1.50-1.58 (m, 1H); 1.73-1.82 (m, 2H); 1.85-2.02 (m, 2H); 2.04 (s, 6H); 2.13-2.18 (m, 1H); 2.30 (s, 2H); 3.02 (s, 2H); 5.41 (br s, 1H); 7.27-7.32 (m, 3H); 7.36-7.41 (m, 2H).

¹³C-NMR (CDCl₃): 30.2; 32.9; 38.0; 38.1; 39.2; 42.4; 53.9; 60.4; 126.6; 127.5; 127.7; 136.3; 177.6.

LC-MS: m/z: [M+H]⁺=273.3, R_(t)=1.6 min.

Example No. 16 8-Butyl-8-dimethylamino-8-phenyl-3-azaspiro[4.5]decan-4-one (Example no 16, a diastereomer)

A solution of dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (390 mg, 1.76 mmol) in tetrahydrofuran (15 ml) was added dropwise to a 2 M solution of n-butylmagnesium chloride in tetrahydrofuran (3.5 ml, 7 mmol) at 0° C. and under argon and thereafter the mixture was stirred overnight at room temperature. 20% strength ammonium chloride solution (15 ml) was then added to the reaction solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (334 mg) was purified by flash chromatography (32 g, 20×2.5 cm) with methylene chloride/methanol [9:1→4:1→4:1+1% ammonia (33% in H₂O)]. Thereafter the mixed fractions were purified by renewed flash chromatography (12 g, 18×1.6 cm) with methylene chloride/methanol [9:1+0.5% ammonia (33% in H₂O)].

Example No. 16 A Diastereomer

Yield: 185 mg (42%), white solid

Melting point: 148-151° C.

¹H-NMR (CDCl₃): 0.89 (t, 3H, J=7.1 Hz); 1.08-1.35 (m, 10H); 1.71 (br d, 2H, J=13.0 Hz); 1.98 (t, 2H, J=6.9 Hz); 2.06 (dt, 2H, J=13.0 Hz); 2.20 (s, 6H); 3.23-3.31 (m, 2H); 6.85 (s, 1H).

¹³C-NMR (CDCl₃): 14.1; 23.8 (2C); 26.7; 27.3; 28.4; 31.0 (2C); 32.3; 37.1 (2C); 39.0; 43.6; 55.9; 183.5.

LC-MS: m/z: [M+H]⁺=253.3, R_(t)=1.5 min.

Example No. 17 8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one (Example no. 17, a diastereomer)

A solution of dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (800 mg, 3.6 mmol) in tetrahydrofuran (15 ml) was added dropwise to a 1 M solution of 2-thienylmagnesium bromide in tetrahydrofuran (11.5 ml, 11.5 mmol) at 0° C. and under argon and thereafter the mixture was stirred overnight at room temperature. 20% strength ammonium chloride solution (35 ml) was then added to the reaction solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were dried with sodium sulfate and concentrated. The crude product (950 mg) was purified by flash chromatography (80 g, 17×3.7 cm) with methylene chloride/methanol [9:1+2% ammonia (33% in H₂O)].

Example No. 17 A Diastereomer

Yield: 840 mg (84%), yellowish solid

Melting point: 168-174° C.

¹H-NMR (CDCl₃): 1.26-1.36 (m, 2H); 1.69 (dt, 2H, J=3.2 and 13.8 Hz); 1.99 (t, 2H, J=6.9 Hz); 2.10 (s, 6H); 2.20 (dt, 2H, J=3.2 and 13.1 Hz); 2.45 (br d, 2H, J=13.6 Hz); 3.25-3.34 (m, 2H); 6.76 (br s, 1H); 6.85 (dd, 1H, J=1.1 and 3.6 Hz); 7.03 (dd, 1H, J=3.6 and 5.1 Hz); 7.21 (dd, 1H, J=1.1 and 5.1 Hz).

¹³C-NMR (CDCl₃): 27.9 (2C); 31.9 (2C); 32.5; 38.0 (2C); 38.9; 43.4; 58.4; 122.8; 123.6; 126.0; 145.4; 183.0.

LC-MS: m/z: [M+H]⁺=279.2, R_(t)=1.3 min.

Example No. 18 Dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (Example no. 18, polar diastereomer)

A solution of 8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one (polar diastereomer) (714 mg, 2.56 mmol) in tetrahydrofuran (20 ml) was added to a suspension of lithium aluminium hydride (490 mg, 12.9 mmol) in tetrahydrofuran (4 ml) at room temperature and the mixture was stirred for 18 h at 60° C. The reaction mixture was cooled to 0° C., water (0.5 ml), 1 N sodium hydroxide solution (1 ml) and again water (1 ml) were added and the mixture was then stirred for 1 h at room temperature. The precipitate was filtered off, ethyl acetate (20 ml) was added to the filtrate and the phases were separated. The organic phase was dried with sodium sulfate and the solvent was removed i. vac. The residue (570 mg) was purified by flash chromatography (30 g, 19×2.5 cm) with methylene chloride/methanol (4:1) and 1% ammonia (25% in H₂O).

Example No. 18 Polar Diastereomer

Yield: 280 mg (41%), white oily solid.

Melting point: 80-84° C.

¹H-NMR (CDCl₃): 1.38 (ddd, 2H, J=3.6, 13.3 Hz); 1.43-1.50 (m, 1H); 1.58-1.70 (m, 2H); 1.86-2.01 (m, 2H); 2.09 (m, 9H); 2.75 (s, 2H); 2.90 (t, 2H, J=7.1 Hz); 6.84 (dd, 1H, J=1.1 and 3.6 Hz); 7.03 (dd, 1H, J=3.6 and 5.1 Hz); 7.23 (dd, 1H, J=1.1 and 5.1 Hz). The NH proton could not be identified.

¹³C-NMR (CDCl₃): 32.8 (2C); 33.7 (2C); 38.1; 39.0; 42.3; 57.8; 59.8; 123.2; 124.9; 126.1; 143.2.

LC-MS: m/z: [M+H]⁺=265.2, R_(t)=0.5 min.

Example No. 19 Dimethyl-(3-methyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (Example no. 19, polar diastereomer)

37% strength aqueous formalin solution (1 ml) and sodium cyanoborohydride (151 mg, 2.4 mmol) were added to a solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (polar diastereomer) (160 mg, 0.6 mmol) in methanol (6 ml) and the mixture was stirred for 30 min at room temperature. After addition of acetic acid (0.6 ml) the mixture was further stirred for 3 h at room temperature. The reaction solution was then diluted with saturated sodium bicarbonate solution (20 ml) and extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate, the solvent was removed i. vac. and the residue (164 mg) was purified by flash chromatography (16 g, 16×2 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in H₂O).

Example No. 19 Polar Diastereomer

Yield: 90 mg (54%), white solid

Melting point: 71-72° C.

¹H-NMR (CDCl₃): 1.34-1.43 (m, 2H); 1.52 (t, 2H, J=6.8 Hz); 1.64-1.75 (m, 2H); 1.84-1.99 (m, 2H); 2.08 (s, 8H); 2.30 (s, 3H); 2.40 (s, 2H); 2.48 (t, 2H, J=6.8 Hz); 6.83 (dd, 1H, J=1.0 and 3.5 Hz); 7.02 (dd, 1H, J=3.5 and 5.1 Hz); 7.21 (dd, 1H, J=1.0 and 5.1 Hz).

¹³C-NMR (CDCl₃): 33.6 (2C); 34.4; 38.1 (2C); 38.6 (br.); 41.7; 42.6 (2C); 55.9; 59.6; 68.1 (br.); 74.8; 132.2; 124.9; 126.1; 143.3 (br).

LC-MS: [MH-HNMe₂]⁺: m/z=234.2 (100%) and [M+H]⁺: m/z=279.3 (8%), R_(t)=0.2 min.

Example No. 20a 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-butan-1-one (Example no. 20a, polar diastereomer)

Butyryl chloride (69 mg, 68 μl, 0.65 mmol) was added to a solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (polar diastereomer) (142 mg, 0.54 mmol) and triethylamine (82 mg, 0.81 mmol) in methylene chloride (5 ml) and the mixture was stirred for 2.5 h at room temperature. 1 M potassium carbonate solution (6 ml) was then added to the reaction mixture and the mixture was stirred for 30 min at room temperature. The phases were separated and the aqueous phase was extracted with methylene chloride (2×10 ml).

The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (180 mg) was purified by flash chromatography (18 g, 19×2 cm) with methylene chloride/methanol (95:5).

Example No. 20a Polar Diastereomer

Yield: 140 mg (78%), colourless oil

¹H-NMR (CDCl₃): 0.96 (ddt, 3H, J=0.6; 4.5 and 7.4 Hz); 1.33-1.45 (m, 2H); 1.57-1.78 (m, 6H); 1.84-2.03 (m, 2H); 2.09 (d, 3H, J=0.7 Hz); 2.12 (s, 4H); 2.22 (dd, 3H, J=6.7 and 14.5 Hz); 3.31 (s, 1H); 3.37 (s, 1H); 3.41-3.50 (m, 2H); 6.83-6.88 (m, 1H); 7.01-7.07 (m, 1H); 7.22-7.26 (m, 1H).

¹³C-NMR (CDCl₃): 14.0; 18.3; 18.4; 31.1; 31.2; 32.8; 33.4; 35.6; 36.3; 36.8; 37.1; 38.1; 40.1; 42.9; 45.0; 55.3; 56.4; 59.9; 123.3; 123.6; 124.9; 125.1; 126.1; 126.4; 171.9; 172.0. Some C signals are doubled due to the amide structure.

LC-MS: [MH-HNMe₂]⁺: m/z=290.2 (100%) and [M+H]⁺: m/z=335.3 (90%), R_(t)=2.7 min.

Example No. 20b 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-butan-1-one (Example no. 20b, non-polar diastereomer)

Butyryl chloride (63 mg, 62 μl, 0.59 mmol) was added to a solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (non-polar diastereomer) (130 mg, 0.49 mmol) and triethylamine (75 mg, 103 μl, 0.74 mmol) in methylene chloride (5 ml) and the mixture was stirred for 1 h at room temperature. Potassium carbonate solution (5 ml) was then added to the mixture and the mixture was stirred for 15 min.

The phases were separated and the aqueous phase was subsequently extracted with methylene chloride (3×5 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (160 mg) was purified by means of flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (95:5).

Example No. 20b Non-Polar Diastereoisomer

Yield: 116 mg (71%), yellow oil

¹H-NMR (CDCl₃): 0.91 (t, 1.5H, J=7.4 Hz); 0.96 (t, 1.5H, J=7.4 Hz); 1.37-1.45 (m, 2H); 1.57-1.73 (m, 4H); 1.76 (t, 1H, J=7.2 Hz); 1.86 (t, 1H, J=7.2 Hz); 2.00-2.09 (m, 4H); 2.12 (s, 6H); 2.13-2.23 (m, 2H); 3.14 (s, 1H); 3.23 (s, 1H); 3.47 (t, 1H, J=7.1 Hz); 3.52 (t, 1H, J=7.1 Hz); 6.84 (dd, 0.5H, J=0.8, 3.6 Hz); 6.86 (dd, 0.5H, J=1.1, 3.6 Hz); 7.02 (dd, 0.5H, J=3.6, 5.2 Hz); 7.04 (dd, 0.5H, J=3.6, 5.2 Hz); 7.22 (dd, 0.5H, J=0.8, 5.1 Hz); 7.24 (dd, 0.5H, J=1.1, 5.1 Hz).

¹³C-NMR (CDCl₃): 13.97; 13.99; 18.4; 31.0; 33.1; 36.3; 36.7, 38.07; 38.09, 40.1; 42.1; 44.1; 45.2; 56.0; 57.6; 59.9; 123.5; 124.9; 126.21, 126.26; 171.8; 171.9.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [MH-HNMe₂]⁺=290.2 (100%) and [M+H]⁺=335.3 (50%), R_(t)=2.7 min.

Example No. 21 (3-Butyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 21, polar diastereomer)

Butyraldehyde (49 mg, 61 μl, 0.68 mmol) and sodium cyanoborohydride (147 mg, 2.34 mmol) were added to a cloudy solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (polar diastereomer) (137 mg, 0.52 mmol) in methanol (5 ml) and the mixture was stirred for 30 min at room temperature. After addition of acetic acid (0.52 ml) the mixture was stirred for a further 2 h at room temperature. The reaction mixture was then diluted with sodium bicarbonate solution (20 ml) and extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (157 mg) was purified by means of flash chromatography (16 g, 16×2.0 cm) with methanol and 0.5% ammonia (25% in H₂O).

Example No. 21 Polar Diastereomer

Yield: 105 mg (63%), colourless oil

¹H-NMR (CDCl₃): 0.91 (t, 3H, J=7.2 Hz); 1.27-1.53 (m, 8H); 1.64-1.74 (m, 2H); 1.85-1.99 (m, 2H); 2.10 (m, 8H); 2.33-2.40 (m, 2H); 2.42 (s, 2H); 2.50 (t, 2H, J=6.9 Hz); 6.85 (td, 1H, J=1.0 and 3.6 Hz); 7.02-7.05 (m, 1H); 7.21-7.24 (m, 1H).

¹³C-NMR (CDCl₃): 14.1; 20.9; 31.0; 33.8; 34.5; 38.2; 40.8; 54.0; 56.8; 59.7; 65.6; 123.2; 124.9; 126.1. A thienyl-C signal (approx. 143 ppm) could not be identified.

LC-MS: [MH-HNMe₂]⁺: m/z=276.3 (100%) and [M+H]⁺: m/z=321.3 (16%), R_(t)=0.3 min.

Example No. 22 [3-(Cyclopentylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine (Example no. 22, polar diastereomer)

A solution of cyclopentanecarbaldehyde (92 mg, 0.94 mmol) in methanol (1 ml) and sodium cyanoborohydride (204 mg, 3.24 mmol) was added to a cloudy solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (polar diastereomer) (190 mg, 0.72 mmol) in methanol (6 ml) and the mixture was stirred for 30 min at room temperature. After addition of acetic acid (0.72 ml) the mixture was stirred for a further 3 h at room temperature. The reaction mixture was then diluted with sodium bicarbonate solution (30 ml) and extracted with methylene chloride/2-propanol (4:1, 2×30 ml) and methylene chloride (30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (357 mg) was purified by means of flash chromatography (35 g, 22×2.5 cm) with methanol and 0.2% ammonia (25% in H₂O).

Example No. 22 Polar Diastereomer

Yield: 179 mg (72%), colourless oil

¹H-NMR (CDCl₃): 1.13-1.24 (m, 2H); 1.37 (ddd, 2H, J=3.5; 10.0 and 13.3 Hz); 1.44-1.63 (m, 6H); 1.64-1.81 (m, 4H); 1.84-2.03 (m, 3H); 2.10 (s, 8H); 2.31 (d, 2H, J=7.3 Hz); 2.41 (5, 2H); 2.49 (t, 2H, J=6.9 Hz); 6.85 (dd, 1H, J=1.1 and 3.6 Hz); 7.03 (dd, 1H, J=3.6 and 5.1 Hz); 7.22 (dd, 1H, J=1.1 and 5.1 Hz).

¹³C-NMR (CDCl₃): 25.2 (2C); 31.5 (2C); 33.7 (2C); 34.3 (2C); 37.7; 38.2; 39.1; 41.0; 54.3; 59.7; 62.5; 65.6; 123.2; 124.9; 126.1; 143.2.

LC-MS: [MH-HNMe₂]⁺: m/z=302.3 (100%) and [M+H]⁺: m/z=347.3 (30%), R_(t)=1.9 min.

Example No. 24a and Example No. 24b Step 1: (4-Dimethylamino-4-thiophen-2-ylcyclohexylidene)-acetic acid ethyl ester

Potassium tert-butylate (3.01 g, 26.9 mmol) was added to a solution of triethyl phosphonoacetate (6.02 g, 5.33 ml, 26.9 mmol) in absolute N,N-dimethylformamide (30 ml) under argon. The mixture was stirred for 10 min at room temperature, before a solution of 4-(dimethylamino)-4-(thiophen-2-yl)cyclohexanone (4.0 g, 17.9 mmol) in absolute N,N-dimethylformamide (60 ml) was added, and the mixture was then stirred for 1 h at room temperature. The reaction mixture was then poured into ice-water (75 g) and the aqueous suspension was extracted with diethyl ether (4×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 5.20 g (99%), yellow oil

¹H-NMR (CDCl₃): 1.26 (t, 3H, J=7.1 Hz); 2.03-2.12 (m, 2H); 2.13 (s, 6H); 2.15-2.27 (m, 2H); 2.90-3.09 (m, 4H); 4.13 (q, 2H, J=7.1 Hz); 5.61 (s, 1H); 6.87 (dd, 1H, J=1.1, 3.6 Hz); 7.03 (dd, 1H, J=3.6, 5.1 Hz); 7.23 (dd, 1H, J=1.1, 5.1 Hz).

LC-MS: m/z: [MH-HNMe₂]⁺=249.2 (90%), R_(t)=2.8 min.

Step 2: (4-Dimethylamino-1-nitromethyl-4-thiophen-2-yl-cyclohexyl)-acetic acid ethyl ester

Tetra-n-butylammonium fluoride trihydrate (5.10 g, 19.5 mmol) and nitromethane (5.40 g, 4.79 ml, 88.5 mmol) were added to a solution of the crude product of (4-dimethylamino-4-thiophen-2-ylcyclohexylidene)-acetic acid ethyl ester (5.20 g, 17.7 mmol) in tetrahydrofuran (120 ml) and the mixture was stirred for 3 h at 70° C. and then for 18 h at 45° C. The reaction mixture was then concentrated i. vac. The residue was purified by means of flash chromatography (200 g, 20×4.0 cm) with cyclohexane/ethyl acetate (1:9).

Yield: 4.9 g (78%), orange-coloured oil

¹H-NMR (CDCl₃): 1.20-1.28 (m, 3H); 1.44-1.53 (m, 4H); 1.77-1.88 (m, 4H); 2.09 (s, 6H); 2.46 and 2.61 (2 s, 2H); 4.04-4.22 (m, 2H); 4.62 and 4.77 (s, 2H); 6.82-6.85 (m, 1H); 7.02 (m, 1H); 7.22-7.25 (m, 1H).

LC-MS: m/z: [M+H]⁺=355.2, R_(t)=2.5 min.

This is a diastereoisomer mixture in the ratio of approx. 1:1 which is still contaminated with approx. 15% of educt.

Step 3: 8-(Dimethylamino)-8-thiophenyl-2-yl-3-azaspiro[4.5]decan-3-one (Example no. 30, polar diastereomer, Example no. 31, non-polar diastereomer)

A solution of the diastereoisomer mixture of (4-dimethylamino-1-nitromethyl-4-thiophen-2-ylcyclohexyl)-acetic acid ethyl ester (4.90 g, 13.8 mmol) in ethanol (138 ml) was added to a mixture of iron powder (3.85 g, 69 mmol) and ammonium chloride (18.5 g, 345 mmol) in water (14 ml) and the mixture was heated for 5 h under reflux. The reaction mixture was then filtered, saturated sodium bicarbonate solution (4 ml) was added to the filtrate and the mixture was concentrated i. vac. The residue was separated by flash chromatography (200 g, 20×5.7 cm) with methylene chloride/methanol (10:1) and 1% ammonia (32% in water).

Yield: 2.33 g (61%), diastereoisomer mixture in the ratio of approx. 1:1

The diastereoisomer mixture was separated by repeated medium pressure chromatography (230 g, 3.6×46 cm) or flash chromatography (100 g, 20×4.0 cm), the column material used being spherical silica gel (PharmPrep 60 CC (40-63 μm) and the eluent used being methylene chloride/methanol 95:5 and 1% ammonia (32% in H₂O). The ratio of sample to silica gel weight was in each case approx. 1:200.

Example No. 24a Polar Diastereomer

Melting point: 215° C., white solid

¹H-NMR (CDCl₃): 1.47-1.55 (m, 2H); 1.78-1.86 (m, 2H); 1.97-2.09 (m, 4H); 2.10 (s, 6H); 2.12 (s, 2H); 3.23 (s, 2H); 5.69 (br s, 1H); 6.85 (dd, 1H, J=1.1, 3.6 Hz); 7.05 (dd, 1H, J=3.6, 5.1 Hz); 7.25 (dd, 1H, J=1.2, 5.1 Hz).

¹³C-NMR (CDCl₃): 32.6; 32.7, 38.1; 38.8; 43.1; 53.0; 59.3; 123.4; 124.9; 126.3; 142.6; 177.5.

LC-MS: m/z: [MH-HNMe₂]⁺=234.2 (100%) and [M+H]⁺=279.2 (16%), R_(t)=1.3 min.

Example No. 24b Non-Polar Diastereoisomer

Melting point: 213-222° C., white solid

¹H-NMR (CDCl₃): 1.46-1.54 (m, 2H); 1.76-1.84 (m, 2H); 1.93-2.12 (m, 4H); 2.09 (s, 6H); 2.26 (s, 2H); 3.08 (s, 2H); 5.78 (br s, 1H); 6.85 (dd, 1H, J=1.1, 3.6 Hz); 7.04 (dd, 1H, J=3.6, 5.1 Hz); 7.24 (dd, 1H, J=1.1, 5.1 Hz).

¹³C-NMR (CDCl₃): 32.7; 32.8; 38.1; 38.9; 42.5; 53.6; 59.5; 123.4; 124.8; 124.9; 126.3; 142.7; 177.5.

LC-MS: m/z: [MH-HNMe₂]⁺=234.2 (100%) and [M+H]⁺=279.2 (22%), R_(t)=1.4 min.

Example No. 26 Dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (Example no. 25, non-polar diastereomer)

A solution of 8-dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one (non-polar diastereomer) (270 mg, 0.97 mmol) in absolute tetrahydrofuran (15 ml) was added to a suspension of lithium aluminium hydride (184 mg, 4.85 mmol) in absolute tetrahydrofuran (10 ml), while cooling with ice, and the mixture was stirred for 18 h at 60° C. Water (755 μl), 1 N sodium hydroxide solution (2.5 ml) and again water (2.5 ml) were then added to the mixture, while cooling with ice, and the mixture was stirred for 1 h at room temperature. The suspension was filtered through sea sand and the residue was washed with tetrahydrofuran. The filtrate was dried with sodium sulfate and concentrated i. vac. The crude product (300 mg) was purified by means of flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (4:1)+1% ammonia (25% in H₂O)→methanol+1% ammonia (25% in H₂O).

Example No. 25 Non-Polar Diastereoisomer

Yield: 182 mg (71%), yellow oil

¹H-NMR (CDCl₃): 1.37 (ddd, 2H, J=3.5, 10.1, 13.5 Hz); 1.57-1.65 (m, 4H); 1.89-1.99 (m, 2H); 2.06-2.15 (m, 3H); 2.10 (s, 6H); 2.57 (s, 2H); 2.93 (t, 2H, J=7.1 Hz); 6.84 (dd, 1H, J=1.1, 3.6 Hz); 7.02 (dd, 1H, J=3.6, 5.1 Hz); 7.22 (dd, 1H, J=1.1, 5.1 Hz).

¹³C-NMR (CDCl₃): 32.9; 33.8; 38.2; 38.4; 42.4; 46.6; 59.4; 59.9; 123.2; 125.0; 126.1; 143.0.

LC-MS: m/z: [MH-HNMe₂]⁺=220.2 (100%) and [M+H]⁺=265.3 (48%), R_(t)=0.2 min.

Example No. 27 (8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (Example no. 27, polar diastereomer)

Sodium cyanoborohydride (177 mg, 2.82 mmol) and butyraldehyde (86 mg, 106 μl, 1.19 mmol) were added to a solution of (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine (polar diastereomer) (162 mg, 0.59 mmol) in methanol (5 ml) and the mixture was stirred for 30 min at room temperature. After addition of glacial acetic acid (600 μl) the mixture was stirred for a further 2 h at room temperature. Thereafter saturated sodium bicarbonate solution (20 ml) was added and the solution was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 27 Polar Diastereoisomer

Yield: 158 mg (93%), colourless oil

¹H-NMR (CDCl₃): 0.88 (t, 3H, J=7.3 Hz); 1.06-1.16 (m, 2H); 1.22-1.34 (m, 4H); 1.38-1.47 (m, 2H); 1.60 (t, 2H, J=6.9 Hz); 1.64-1.74 (m, 4H); 2.21 (s, 2H); 2.29 (s, 6H); 2.35-2.41 (m, 2H); 2.58 (t, 2H, J=6.9 Hz); 2.62 (s, 2H); 7.10-7.13 (m, 2H); 7.16-7.28 (m, 3H).

¹³C-NMR (CDCl₃): 13.9; 20.7; 30.1; 30.3; 33.0; 36.8; 37.2; 39.7; 40.9; 53.2; 56.7; 57.5; 64.3; 125.6; 127.9; 130.7; 139.3.

LC-MS: m/z: [M+H]⁺=329.4, R_(t)=0.9 min.

Example No. 28 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-butan-1-one (Example no. 28, non-polar diastereomer)

Triethylamine (193 mg, 264 μl, 1.9 mmol) and butyryl chloride (134 mg, 132 μl, 1.26 mmol) were added to a solution of N,N-dimethyl-8-phenyl-3-azaspiro[4.5]decan-8-amine (non-polar diastereomer) (160 mg, 0.62 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 20 h at room temperature. After addition of methylene chloride (20 ml) the solution was washed with 25% strength potassium carbonate solution (2×20 ml) and the organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (205 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 28 Non-Polar Diastereoisomer

Yield: 106 mg (50%), colourless oil

¹H-NMR (CDCl₃): 0.90 and 0.95 (2 t, 3H, J=7.4 Hz); 1.28-1.39 (m, 2H); 1.56-1.70 (m, 4H); 1.80 and 1.89 (2 t, 2H, J=7.1 Hz); 1.96-2.04 (m, 2H); 2.05 (s, 6H); 2.09-2.23 (m, 4H); 3.08 and 3.17 (2 s, 2H); 3.45-3.55 (m, 2H); 7.26-7.41 (m, 5H).

¹³C-NMR (CDCl₃): 13.96; 14.0; 18.4; 30.4; 30.5; 31.10; 31.11; 34.3; 36.3; 36.7; 38.0; 40.3; 42.3; 44.1; 45.2; 56.4; 58.0; 60.7; 126.7; 127.4; 127.5; 127.6; 127.7; 136.5; 171.8.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=329.4, R_(t)=2.7 min.

Example No. 29 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-butan-1-one (Example no. 29, polar diastereomer)

Triethylamine (235 mg, 322 μl, 2.3 mmol) and butyryl chloride (164 mg, 161 μl, 1.5 mmol) were added to a solution of N,N-dimethyl-8-phenyl-3-azaspiro[4.5]decan-8-amine (polar diastereomer) (200 mg, 0.77 mmol) in anhydrous methylene chloride (5 ml) and the mixture was stirred for 4 h at room temperature. After addition of methylene chloride (20 ml) the solution was washed with 25% strength potassium carbonate solution (2×20 ml) and the organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (260 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 29 Polar Diastereoisomer

Yield: 218 mg (86%), colourless oil

¹H-NMR (CDCl₃): 0.97 (t, 3H, J=7.4 Hz); 1.23-1.35 (m, 2H); 1.52-1.74 (m, 8H); 2.02 and 2.04 (2 s, 6H); 2.18-2.26 (m, 3H); 2.23-2.41 (br s, 1H); 3.34 and 3.41 (2 s, 2H); 3.39-3.48 (m, 2H); 7.23-7.42 (m, 5H).

¹³C-NMR (CDCl₃): 13.7; 14.0; 18.4; 18.5; 18.9; 30.1; 30.9; 31.2; 31.5; 36.4; 36.9; 37.8; 38.0; 38.1; 40.3; 42.3; 43.9; 45.0; 55.1; 56.4; 60.8; 126.5; 126.7; 127.6; 127.63; 127.67; 127.7; 171.9; 172.0.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=329.4, R_(t)=2.8 min.

Example No. 30 Step 1: 8-Cyanomethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester

A 2.5 M solution of n-buyllithium in n-hexane (11 ml, 27.5 mmol) was added dropwise to a solution of diisopropylamine (2.78 g, 3.92 ml, 27.5 mmol) in tetrahydrofuran (50 ml) in a thoroughly heated flask at −78° C. under argon. The reaction solution was stirred for 15 min at 0° C. and then cooled again to −78° C. and a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (5.36 g, 25 mmol) in tetrahydrofuran (7.5 ml) was added dropwise in the course of 20 min. The resulting mixture was stirred for 1.5 h at −78° C. and a solution of bromoacetonitrile (3.58 g, 1.99 ml, 30 mmol) and 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)pyrimidone (DMPU, 1.60 g, 1.5 ml, 12.5 mmol) in tetrahydrofuran (7.5 ml) was then slowly added dropwise. The reaction solution was then warmed to room temperature in the course of approx. 3 h and stirred for a further 20 h at room temperature. Thereafter 0.5 N hydrochloric acid (19 ml) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with diethyl ether (3×50 ml). The combined organic phases were washed with sodium bicarbonate solution (2×100 ml) and with sodium chloride solution (4×100 ml), dried with sodium sulfate and concentrated i. vac. The crude product (5.5 g) was purified by flash chromatography (250 g, 27×5.4 cm) with ethyl acetate/cyclohexane (1:2).

Yield: 3.60 g (57%), colourless oil

¹H-NMR (CDCl₃): 1.29 (t, 3H, J=7.1 Hz); 1.62-1.76 (m, 6H); 2.17-2.29 (m, 2H); 2.57 (s, 2H); 3.93 (t, 4H, J=2.2 Hz); 4.23 (q, 2H, J=7.1 Hz).

Step 2: 1,4-Dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one

Sodium borohydride (2.68 g, 71 mmol) was added in portions to a mixture of 8-cyanomethyl-1,4-dioxaspiro[4.5]decane-8-carboxylic acid ethyl ester (3.6 g, 14.2 mmol) and cobalt(II) chloride (922 mg, 7.1 mmol) in tetrahydrofuran (50 ml) and water (25 ml) at 0° C. under argon. The reaction mixture was stirred for 2 d at room temperature. 25% strength ammonia solution (2.5 ml) was then added to the reaction mixture and the mixture formed was filtered. The residue on the filter was washed with tetrahydrofuran/water (2:1). The filtrate was concentrated i. vac. and the aqueous solution was extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with sodium chloride solution, dried with sodium sulfate and concentrated i. vac.

Yield: 2.50 g (83%), white solid which still contained approx. 15% of educt.

¹H-NMR (CDCl₃): 1.49-1.64 (m, 5H); 1.82-1.91 (m, 2H); 1.96-2.04 (m, 2H); 2.03-2.08 (m, 2H); 3.29-3.34 (m, 2H); 3.95 (s, 4H); 5.51 (br s, 1H).

Step 3: 3-Azaspiro[4.5]decane-4.8-dione

5% strength aqueous sulfuric acid (60 ml) was added to a solution of 1,4-dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one (3.48 g, 16.5 mmol) in acetone (50 ml) and the mixture was stirred for 1 d at room temperature. 1 M potassium carbonate solution (60 ml) was added to the reaction mixture and the mixture was concentrated i. vac. The aqueous solution obtained was extracted with methylene chloride (4×50 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac.

Yield: 2.72 g (98%), white solid

¹H-NMR (CDCl₃): 1.73-1.89 (m, 2H); 2.08-2.21 (m, 4H); 2.33 (ddd, 2H, J=5.8, 10.2 and 15.0 Hz); 2.70 (td, 2H, J=6.3 and 14.8 Hz); 3.41 (dt, 2H, J=0.8 and 7.1 Hz); 3.72 (s, 1H).

Step 4: Dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile

4 N hydrochloric acid (1.97 ml, 7.86 mmol) and then a solution of 3-azaspiro[4.5]decane-4.8-dione (1.09 mg, 6.55 mmol) in methanol (12 ml) were added to a 40° A) strength aqueous dimethylamine solution (3.3 ml, 26.2 mmol), cooled to 0° C., and methanol (1.5 ml). Potassium cyanide (853 mg, 13.1 mmol) was added to this mixture and the mixture was stirred for 20 h at room temperature. After addition of water (30 ml) the solution was extracted with diethyl ether (3×30 ml). The combined organic extracts were dried with sodium sulfate and concentrated, as a result of which the product (390 mg) was isolated. The aqueous solution was then subsequently extracted with methylene chloride (3×20 ml). The combined methylene chloride extracts were dried with sodium sulfate and concentrated, as a result of which 820 mg of the product were obtained.

Yield: 1.21 g (83%), white solid

¹H-NMR (CDCl₃): 1.35-1.67 (m, 3H); 1.76-2.09 (m, 5H); 2.18-2.31 (m, 2H); 2.33 and 2.35 (2s, 6H); 3.28-3.35 (m, 2H); 6.50 and 6.60 (2s, 1H). This is a diastereoisomer mixture in the ratio of approx. 2:1.

Step 5: 8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-4-one (Example no. 42, polar diastereomer)

Magnesium (292 mg, 12 mmol) and an iodine crystal were heated in a secure apparatus under argon until iodine gas evolved. After 10 min absolute diethyl ether (20 ml) and a further iodine crystal were added. The mixture was heated to the boiling point and a solution of 2-bromo-5-methylthiophene (2.12 g, 1.35 ml, 12 mmol) in absolute diethyl ether (20 ml) was then slowly added dropwise such that the solution continued to boil. After the end of the addition the mixture was heated for a further 30 min under reflux and the solution was then cooled to 0° C.

A solution of dimethylamino-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (1.06 g, 4.8 mmol) in absolute tetrahydrofuran (50 ml) was slowly added dropwise to this ice-cooled solution under argon and the mixture was then stirred overnight at room temperature. After addition of saturated ammonium chloride solution (50 ml) the tetrahydrofuran was removed i. vac. The aqueous solution obtained was extracted with methylene chloride (3×50 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac. 160 mg of the crude product (1.56 g) were purified, for the purpose of release, by means of flash chromatography (10 g, 20×1.5 cm) with ethyl acetate/methanol (4:1), as a result of which 139 mg of pure target compound were obtained. This is the polar diastereoisomer. The remainder was reacted further as crude product.

Example No. 30 Polar Diastereoisomer

Yield: 1.56 g (crude product)

Melting point: 173-176° C.

¹H-NMR (CDCl₃): 1.27-1.33 (m, 2H); 1.66 (dt, J=12.9, 3.2 Hz, 2H); 2.00 (t, J=6.9 Hz, 2H); 2.11 (s, 6H); 2.18 (dt, J=13.2, 3.1 Hz, 2H); 2.36-2.43 (m, 2H); 2.46 (s, 3H); 3.27-3.31 (m, 2H); 6.21 (br s, 1H); 6.62 (d, J=3.5 Hz, 1H); 6.65-6.67 (m, 1H).

¹³C-NMR (CDCl₃): 15.2; 28.0; 31.8; 32.6; 37.9; 38.7; 43.3; 58.5; 123.6; 124.7; 137.2; 143.1; 182.8.

LC-MS: m/z: [MH-HNMe₂]⁺=248.2, R_(t)=2.5 min.

Example No. 31 Dimethyl-[8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-amine (Example no. 31, polar diastereomer)

A solution of 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-4-one (polar diastereomer) (1.40 g, 4.8 mmol) in anhydrous tetrahydrofuran (100 ml) was added to a suspension of lithium aluminium hydride (456 mg, 12 mmol) in anhydrous tetrahydrofuran (20 ml) in a thoroughly heated apparatus, while cooling with ice, and the mixture was then stirred at 60° C. overnight. Water (857 μl), 1 N sodium hydroxide solution (2.1 ml) and again water (2.1 ml) were added to the reaction solution, while cooling with ice, and the mixture was stirred for 1 h at room temperature. The mixture was filtered through sea sand and the residue was washed with tetrahydrofuran. The filtrate was dried with sodium sulfate and concentrated i. vac. 160 mg of the crude product (1.18 g) were purified, for the purpose of release, by means of flash chromatography (10 g, 20×1.5 cm) with ethyl acetate methanol (4:1)→methanol+1% ammonia (25% in water), as a result of which 80 mg of the target compound were obtained, which still contained minimal impurities.

Example No. 31 Polar Diastereoisomer

Yield: 1.18 g (crude product), yellow viscous oil

¹H-NMR (CDCl₃): 1.37-1.41 (m, 2H); 1.47 (t, J=7.1 Hz, 2H); 1.57-1.65 (m, 2H); 1.85-1.91 (m, 2H); 2.00-2.16 (m, 2H, overlapped); 2.11 (s, 6H); 2.47 (s, 3H); 2.75 (s, 2H); 2.91 (t, J=7.1 Hz, 2H); 6.62 (d, J=3.5 Hz, 1H); 6.67-6.68 (m, 1H). The NH proton could not be identified.

¹³C-NMR (CDCl₃): 15.3; 32.9; 33.6; 38.2; 42.4; 46.1; 57.9; 59.9; 64.2; 124.3; 124.9; 137.6; 140.8.

LC-MS: m/z: [MH-HNMe₂]⁺=234.2, R_(t)=0.7 min.

Example No. 32 1-[8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-butan-1-one (Example no. 32, polar diastereomer)

Butyryl chloride (91 mg, 90 μl, 0.86 mmol) was added to a solution of 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-4-one (polar diastereomer) (200 mg, 0.72 mmol) and triethylamine (110 mg, 152 μl, 1.1 mmol) in absolute methylene chloride (10 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was then adjusted to pH 9-10 with 1 M potassium carbonate solution and stirred for 15 min. The phases were separated and the aqueous phase was extracted with methylene chloride (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (230 mg) was purified by flash chromatography on spherical silica gel (PharmPrep 60 CC, 40-63 mm, 10 g, 20×1.5 cm) with ethyl acetate/methanol (4:1).

Example No. 32 Polar Diastereoisomer

Yield: 153 mg (63%), colourless viscous oil

¹H-NMR (CDCl₃): 0.94-0.98 (m, 3H); 1.35-1.46 (m, 2H); 1.58-1.71 (m, 6H); 1.81-1.95 (m, 2H); 2.10 (s, 2H); 2.13 (s, 4H); 2.19 (m, 4H); 2.46 (d, J=1.0 Hz, 1H); 2.47 (d, J=1.0 Hz, 2H); 3.30 (s, 1.3H); 3.36 (s, 0.7H); 3.42-3.49 (m, 2H); 6.61 (d, J=3.5 Hz, 0.3H); 6.62 (d, J=3.5 Hz, 0.7H); 6.66 (dd, J=3.4; 1.1 Hz, 0.3H); 6.69 (dd, J=3.4; 1.1 Hz, 0.7H).

¹³C-NMR (CDCl₃): 14.0; 15.3; 18.3; 18.5; 31.2; 31.3; 32.6; 33.3; 36.3; 36.3; 36.9; 37.3; 38.1; 40.1; 42.0; 43.9; 45.0; 55.2; 56.2; 60.1; 60.4; 124.3, 124.6, 124.9; 125.2; 137.7, 138.0; 171.8; 171.9.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [MH-HNMe₂]⁺=304.3, R_(t) 3.0 min.

Example No. 33 3-Butyl-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one (Example no. 33, non-polar diastereomer)

A mixture of 8-(dimethylamino)-8-thiophen-2-yl-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer) (200 mg, 0.72 mmol) and potassium tert-butylate (92 mg, 0.82 mmol) in N,N-dimethylformamide (5 ml) was stirred for 40 min at room temperature, before iodobutane (151 mg, 94 μl, 0.82 mmol) was added and stirring was carried out for a further 18 h at room temperature. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with water (3×10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (190 mg) was purified by means of flash chromatography (10 g, 20×1.5 cm) with methylene chloride methanol (95:5)+1% ammonia (25% in H₂O).

Example No. 33 Non-Polar Diastereoisomer

Yield: 130 mg (54%), yellow oil

¹H-NMR (CDCl₃): 0.89 (t, 3H, J=7.3 Hz); 1.22-1.33 (m, 2H); 1.39-1.50 (m, 4H); 1.70-1.79 (m, 2H); 1.92-2.08 (m, 4H); 2.10 (s, 6H); 2.32 (s, 2H); 3.04 (s, 2H); 3.22 (t, 2H, J=7.3 Hz); 6.84 (dd, 1H, J=1.1, 3.6 Hz); 7.04 (dd, 1H, J=3, 6, 5.1 Hz); 7.24 (dd, 1H, J=1.1, 5.1 Hz).

¹³C-NMR (CDCl₃): 13.7; 20.0; 29.3; 32.7; 32.9; 35.6; 38.1; 42.0; 43.8; 58.6; 59.5; 123.4; 124.9; 126.2; 142.8; 173.5.

LC-MS: m/z: [MH-HNMe₂]⁺=290.3 (100%) and [M+H]⁺=335.3 (33%), R_(t)=2.9 min.

Example No. 34 8-(Dimethylamino)-3-methyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one (Example no. 34, non-polar diastereomer)

A mixture of 8-(dimethylamino)-8-thiophen-2-yl-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer) (200 mg, 0.72 mmol) and potassium tert-butylate (92 mg, 0.82 mmol) in N,N-dimethylformamide (5 ml) was stirred for 40 min at room temperature, before methyl iodide (116 mg, 51 μl, 0.82 mmol) was added and stirring was carried out for a further 5 h at room temperature. Since the reaction was not complete, potassium tert-butylate (40 mg, 0.36 mmol) and methyl iodide (58 mg, 25 μl, 0.41 mmol) were again added and the mixture was stirred for a further 18 h at room temperature. The reaction mixture was then diluted with ethyl acetate (50 ml) and washed with water (3×10 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product was purified by means of flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5)+1% ammonia (25% in H₂O).

Example No. 34 Non-Polar Diastereoisomer

Yield: 124 mg (59%), white solid

Melting point: 88-94° C.

¹H-NMR (CDCl₃): 1.40-1.49 (m, 2H); 1.68-1.78 (m, 2H); 1.90-2.07 (m, 4H); 2.08 (s, 6H); 2.29 (s, 2H); 2.77 (s, 3H); 3.04 (s, 2H); 6.82 (dd, 1H, J=0.9, 3.4 Hz); 7.02 (dd, 1H, J=3.6, 5.0 Hz); 7.21 (dd, 1H, J=0.8, 5.1 Hz).

¹³C-NMR (CDCl₃): 29.5; 32.6; 32.9; 35.3; 38.1; 43.4; 59.4; 61.0; 123.4; 124.9; 126.2; 142.7; 173.7.

LC-MS: m/z: [MH-HNMe₂]⁺=248.2 (100%) and [M+H]⁺=293.3 (50%), R_(t)=2.2 min.

Example No. 35 [3-Butyl-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine (Example no. 35, polar diastereomer)

Butyraldehyde (61 mg, 75 μl, 0.84 mmol), acetic acid (650 μl) and sodium cyanoborohydride (184 mg, 2.9 mmol) were added successively to a solution of dimethyl-[8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl)-amine (polar diastereomer) (180 mg, 0.65 mmol) in absolute methanol (5 ml) and the mixture was stirred for 4 h at room temperature. Saturated potassium bicarbonate solution (30 ml) was then added to the reaction mixture and the mixture was extracted with methylene chloride/2-propanol (4:1) (3×30 ml). The combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac. The residue (186 mg) was purified by flash chromatography on spherical silica gel (PharmPrep 60 CC, 40-63 mm, 10 g, 20×1.5 cm) with methanol which contained 1% ammonia (25% in H₂O).

Example No. 35 Polar Diastereoisomer

Yield: 106 mg (49%), colourless viscous oil

¹H-NMR (CDCl₃): 0.91 (t, J=7.3 Hz, 3H); 1.27-1.52 (m, 8H); 1.62-1.69 (m, 2H); 1.78-1.93 (m, 2H); 2.02-2.05 (m, 2H); 2.11 (s, 6H); 2.34-2.38 (m, 2H); 2.41 (s, 2H); 2.46 (d, J=1.1 Hz, 3H); 2.49 (d, J=6.9 Hz, 2H); 6.61 (d, J=3.5 Hz, 1H); 6.67 (qd, J=3.3, 1.0 Hz, 1H).

¹³C-NMR (CDCl₃): 14.1; 15.3; 20.9; 31.1; 33.6; 34.6; 38.2; 40.8, 54.0; 56.8; 59.8: 65.6; 124.3; 124.9; 137.5.

LC-MS: m/z: [M+H]⁺=335.2, R_(t)=1.6 min.

Example No. 41 1-[8-Dimethylamino-8-(5-methylthiophen-2-yl)-2-azaspiro[4.5]dec-2-yl]-2-methoxyethanone

Dimethyl-[8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-amine (Example no. 31) (0.28 g, 1.00 mmol) and triethylamine (0.33 ml, 2.40 mmol) were dissolved in abs. THF (5 ml) under argon, methoxyacetyl chloride (0.11 ml, 0.13 g, 1.20 mmol) was added and the mixture was stirred at room temperature for 1 d. For working up the reaction mixture was concentrated to dryness i. vac., the residue was taken up in methylene chloride and the mixture was washed with saturated NaHCO₃ solution (2×25 ml) and water (2×25 ml). The organic phase was dried over Na₂SO₄, filtered and concentrated i. vac. The residue obtained was purified by means of a PuriFlash 430 and Interchim cartridge 15 μm×25 g with chloroform/methanol (100:0→0:100).

Yield: 120 mg (34%)

¹H-NMR (CDCl₃): 1.34-1.41 (2H, m); 1.53-1.68 (4H, m); 1.94 (2H, m); 2.10 (2H, s); 2.17 (6H, s); 2.44 (3H, m); 3.27 (1H, s); 3.36-3.41 (4H, m); 3.47 (2H, t); 3.97 (2H, d); 6.64 (2H, m).

Step 2: [3-(2-Methoxyethyl)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine (Example no. 58, polar diastereomer)

LiAlH₄ (26 mg, 0.68 mmol) was added to a solution of 1-[8-dimethylamino-8-(5-methylthiophen-2-yl)-2-azaspiro[4.5]dec-2-yl]-2-methoxyethanone (0.12 g, 0.34 mmol) in abs. THF (5 ml) under argon and the mixture was stirred under reflux for 1 h. For working up the reaction mixture was hydrolysed with a few drops of water at 0° C. The suspension was then subsequently stirred for 1 h. The solution was filtered over a sea sand frit, the sand was rinsed with THF and methylene chloride and the combined solution was concentrated i. vac.

Example No. 41 Polar Diastereoisomer

Yield: 62 mg (54%)

¹H-NMR (CDCl₃): 1.34-1.42 (2H, m); 1.50 (2H, t); 1.66 (2H, m); 1.81 (2H, bs); 2.05 (1H, m); 2.09 (6H, s); 2.45 (5H, s); 2.54 (2H, t); 2.60 (2H, t); 3.33 (3H, s); 3.46 (2H, t); 6.60 (1H, m); 6.65 (1H, m).

LC-MS: m/z: [M+H]⁺=337.2, R_(t)=1.1 min.

Example No. 48 2-Cyclopropyl-1-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethanone (Example no. 48, polar diastereomer)

Carbonyldiimidazole (365 mg, 2.25 mmol) was added to a solution of cyclopropylacetic acid (180 mg, 174 μl, 1.8 mmol) in absolute tetrahydrofuran (20 ml) and the mixture was stirred for 2 h under reflux (evolution of CO₂). A solution of dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine (Example no. 18) (397 mg, 1.5 mmol) in tetrahydrofuran (10 ml) was added to the solution and the mixture was stirred for 2 h under reflux. The reaction mixture was then concentrated i. vac., the residue was dissolved in ethyl acetate (30 ml) and the solution was extracted with water (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product was purified by means of flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (95:5).

Example No. 48 Polar Diastereoisomer

Yield: 280 mg (54%), brown oil

¹H-NMR (CDCl₃): 0.12-0.19 (2H, m); 0.55 (2H, ddd, J=8.1, 5.8 and 4.6 Hz); 1.03-1.14 (1H, m); 1.34-1.45 (2H, m); 1.58-1.63 (1.4 H, m); 1.64-1.72 (3H, m); 1.85-2.03 (2.6 H, m); 2.09 (3H, s); 2.13 (3H, br s); 2.17-2.20 (3H, m); 3.29 (1.2H, s), 3.38 (0.8H, s); 3.41 (0.8H, t, J=7.2 Hz); 3.49 (1.2H, t, J=7.3 Hz); 6.85 (0.4 H, dd, J=3.6 and 1.1 Hz); 6.86-6.88 (0.6 H, m); 7.03 (0.4 H, dd, J=5.1 and 3.5 Hz); 7.06 (0.6 H, dd, J=5.1 and 3.6 Hz); 7.23 (0.4 H, dd, J=5.1 and 1.1 Hz); 7.24-7.28 (0.6 H, m).

¹³C-NMR (CDCl₃): 4.4; 4.4; 6.8; 6.9; 31.1; 31.2; 32.8; 33.0; 33.3; 35.6; 37.2; 38.0; 38.1; 39.5; 39.9; 40.0; 42.0; 43.9; 45.0; 55.3; 56.4; 60.0; 123.4; 123.8; 124.9; 125.4; 126.1; 126.4; 143.5; 171.4; 171.5.

The NMR spectra show sometimes a doubled signal set (rotamers).

LC-MS: m/z: [MH-HNMe₂]⁺=302.3 (100%) and [M+H]⁺=347.3 (50% R_(t)=2.8 min.

Example No. 92 8-(Cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one (Example no. 92, a diastereoisomer)

A 0.5 M solution of cyclohexylmethylmagnesium bromide in tetrahydrofuran (63.2 ml, 31.6 mmol) was added dropwise to a solution of 8-(dimethylamino)-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (2 g, 9.03 mmol) in anhydrous tetrahydrofuran (75 ml) at 0° C. and the mixture was stirred for 18 h at room temperature. Saturated ammonium chloride solution (90 ml) was then added to the mixture, while cooling with ice. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×25 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (2.4 g) was purified by flash chromatography (200 g, 20×5.7 cm) with methylene chloride/methanol (98:2) and 1% ammonia (25% in water).

Example No. 92 A Diastereoisomer

Yield: 1.20 g (46%), white solid

Melting point: 190-193° C.

¹H-NMR (CDCl₃): 0.88-1.00 (2H, m); 1.06-1.27 (8H, m); 1.32 (2H, dt, J=14.1 and 3.4 Hz); 1.54-1.74 (7H, m); 2.03 (2H, t, J=7.0 Hz); 2.08 (2H, dt, J=13.2 and 3.2 Hz); 2.16 (6H, s); 3.26-3.31 (2H, m); 6.04 (1H, br s).

¹³C-NMR (CDCl₃): 26.2; 26.7; 27.0; 28.9; 32.0; 32.9; 33.5; 36.0; 36.9; 37.7; 38.1; 38.8; 43.8; 56.4; 183.5.

Only one diastereoisomer was isolated.

LC-MS: m/z: [M+H]⁺=293.2, low UV activity.

Example No. 93 Step 1: (8-Cyclohexylmethyl-2-azaspiro[4.5]dec-8-yl)dimethylamine

A solution of 8-(cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one (Example no. 158, a diastereoisomer) (1.05 g, 3.59 mmol) in anhydrous tetrahydrofuran (40 ml) was added dropwise to a suspension of lithium aluminium hydride (683 mg, 18 mmol) in anhydrous tetrahydrofuran (20 ml), while cooling with ice. The mixture was stirred for 18 h at 50° C. and water (700 μl), 1 N sodium hydroxide solution (1.4 ml) and again water (1.4 ml) were then added dropwise, while cooling with ice. The suspension was stirred for 1 h at room temperature and thereafter filtered through sodium sulfate. The residue on the filter was washed with tetrahydrofuran and the filtrate was concentrated i. vac.

Yield: 884 mg (99%), colourless oil

¹H-NMR (CDCl₃): 0.89-1.01 (2H, m); 1.06-1.45 (9H, m); 1.50-1.74 (10H, m); 1.80-1.90 (2H, m); 2.17 (6H, s); 2.64 (2H, s); 2.94 (2H, t, J=7.1 Hz). The NH proton could not be identified.

Step 2: 1-[8-(Cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-butan-1-one (Example no. 159, a diastereomer)

Butyryl chloride (193 mg, 190 μl, 1.80 mmol) was added to a solution of (8-cyclohexylmethyl-2-azaspiro[4.5]dec-8-yl)dimethylamine (420 mg, 1.5 mmol) and triethylamine (230 mg, 315 μl, 2.26 mmol) in anhydrous methylene chloride (15 ml) and the mixture was stirred overnight at room temperature. 25% strength potassium carbonate solution (15 ml) was then added to the mixture and the mixture was stirred for 15 min at room temperature. The phases were separated and the aqueous phase was extracted with methylene chloride (3×5 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (515 mg) was purified by flash chromatography (38 g, 20×2.8 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 93 A Diastereoisomer

Yield: 448 mg (85%), colourless oil

¹H-NMR (CDCl₃): 0.88-1.01 (5H, m); 1.05-1.46 (10H, m); 1.52-1.91 (13H, m); 2.157 and 2.164 (6H, 2 s); 2.12-2.25 (2H, m); 3.17 (1.2H, s); 3.25 (0.8H, s); 3.46 (0.8H, t, J=7.1 Hz); (1.2H, t, J=7.2 Hz).

¹³C-NMR (CDCl₃): 14.0; 18.4; 18.5; 26.2; 26.5; 28.7; 29.2; 29.8; 30.3; 33.1; 33.2; 35.9; 36.1; 36.2; 36.8; 37.1; 37.7; 37.9; 40.3; 42.0; 44.3; 45.2; 57.1; 57.2; 59.5; 171.77; 171.84.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=349.3, low UV activity.

Example No. 9 Step 1: 8-Cyclopentylmethyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one

A solution of 8-(dimethylamino)-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (1.96 g, 8.8 mmol) in anhydrous tetrahydrofuran (40 ml) was added dropwise to a solution of cyclopentylmethylmagnesium iodide (approx. 32 mmol) under an argon atmosphere at 0° C. The reaction mixture was stirred for 18 h at room temperature and saturated ammonium chloride solution (80 ml) was then added, while cooling with ice. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (1.88 g) was purified by flash chromatography (100 g, 20×4.0 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Yield: 519 mg (21%), white solid

¹H-NMR (CDCl₃): 0.98-1.10 (2H, m); 1.10-1.17 (2H, m); 1.30-1.40 (4H, m); 1.42-1.84 (9H, m); 2.01 (2H, t, J=6.9 Hz); 2.17 (6H, s); 3.28 (2H, dd, J=13.9 and 0.8 Hz); 6.51 (1H, s).

¹³C-NMR (CDCl₃): 25.2; 27.2; 29.1; 32.2; 35.3; 36.1; 36.9; 38.9; 43.8; 56.2; 183.3.

Step 2: (8-Cyclopentylmethyl-2-azaspiro[4.5]dec-8-yl)dimethylamine

A solution of 8-cyclopentylmethyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one (539 mg, 1.93 mmol) in anhydrous tetrahydrofuran (20 ml) was added dropwise to a suspension of lithium aluminium hydride (368 mg, 9.7 mmol) in anhydrous tetrahydrofuran (10 ml), while cooling with ice. The mixture was stirred for 18 h at 50° C. and thereafter water (377 μl), 1 N sodium hydroxide solution (754 μl) and again water (754 μl) were added dropwise, while cooling with ice. The suspension was stirred for 1 h at room temperature and then filtered through sodium sulfate, the residue on the filter was washed with tetrahydrofuran and the filtrate was concentrated i. vac.

Yield: 463 mg (90%), colourless oil

¹H-NMR (CDCl₃): 1.00-1.12 (2H, m); 1.17-1.27 (2H, m); 1.31-1.95 (17H, m); 2.18 (6H, s); 2.64 (2H, s); 2.93 (2H, t, J=7.0 Hz). The NH signal could not be identified.

¹³C-NMR (CDCl₃): 25.0; 29.8; 31.8; 35.1; 36.0; 36.7; 37.2; 37.4; 42.6; 46.6; 56.9; 60.7.

Step 3 [3-Butyl-8-(cyclopentylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine (Example no. 164, a diastereomer)

Butyryl chloride (114 mg, 112 μl, 1.07 mmol) was added to a solution of (8-cyclopentylmethyl-2-azaspiro[4.5]dec-8-yl)dimethylamine (237 mg, 0.89 mmol) and triethylamine (136 mg, 187 μl, 1.34 mmol) in anhydrous methylene chloride (10 ml) and the mixture was stirred for 18 h at room temperature. 25% strength potassium carbonate solution (9 ml) was added to the mixture and the mixture was stirred for 15 min at room temperature. The phases were separated and the aqueous phase was extracted with methylene chloride (2×15 ml). The combined organic phases were dried with sodium sulfate and concentrated vac. The residue (307 mg) was purified by flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 95 A Diastereoisomer

Yield: 206 mg (68%), colourless oil

¹H-NMR (CDCl₃): 0.94 (1.5 H, t, J=7.4 Hz); 0.95 (1.5 H, t, J=7.4 Hz); 1.00-1.14 (2H, m); 1.20-1.30 (2H, m); 1.32-1.84 (20H, m); 2.10-2.24 (7H, m); 3.17 (1H, s); 3.25 (1H, s); 3.45 (1H, t, J=7.2 Hz); 3.50 (1H, t, J=7.2 Hz).

¹³C-NMR (CDCl₃): 14.0; 18.4; 25.1; 28.8; 29.5; 29.8; 30.2; 33.0; 35.0; 35.1; 35.2; 35.5; 35.7; 36.1; 36.2; 36.5; 36.8; 36.9; 37.0; 37.2; 40.3; 42.2; 44.3; 45.3; 56.7; 56.8; 57.1; 59.5; 171.76; 171.84.

The NMR spectra show sometimes doubled signal sets (rotamers).

LC-MS: m/z: [M+H]⁺=335.3, low UV activity.

Example No. 106 and Example No. 107 Step 1: 10-Butyl-1,4-dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one

Potassium tert-butylate (3.19 g, 28.4 mmol) was added to a solution of substance D (equation 1) (5.0 g, 23.7 mmol) in N,N-dimethylformamide (40 ml), whereupon a precipitate precipitated out, and the mixture was then stirred for 30 min at room temperature. n-Butyl iodide (5.23 g, 3.23 ml, 28.4 mmol) was then added to the suspension and the mixture was stirred for 18 h at room temperature. The reaction mixture was then concentrated i. vac., the residue was taken up in ethyl acetate (100 ml) and the solution was washed with water (3×40 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Yield: 5.30 g (84%), yellow oil

¹H-NMR (CDCl₃): 0.91 (3H, t, J=7.3 Hz); 1.22-1.34 (2H, m); 1.42-1.50 (4H, m); 1.53-1.62 (2H, m); 1.81-1.88 (2H, m); 1.91 (2H, t, J=6.9 Hz); 1.93-2.02 (2H, m); 3.26 (4H, t, J=7.0 Hz); 3.92-3.95 (4H, m).

LC-MS: m/z: [M+H]⁺=268.3, R_(t)=3.3 min.

Step 2: 10-Butyl-1,4-dioxa-10-azadispiro[4.2.4.2]tetradecane

A solution of 10-butyl-1,4-dioxa-10-azadispiro[4.2.4.2]tetradecan-9-one (5.22 g, 19.5 mmol) in absolute tetrahydrofuran (40 ml) was added to a suspension of lithium aluminium hydride (2.95 g, 77.8 mmol) in absolute tetrahydrofuran (20 ml), while cooling with ice, and the mixture was stirred for 66 h at 50° C. Water (2.95 ml), 15% strength sodium hydroxide solution (2.95 ml) and again water (8.85 ml) were then cautiously added to the mixture, while cooling with ice, and the mixture was stirred for 1 h at room temperature. The suspension was filtered through sea sand and the residue was washed with tetrahydrofuran. The filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 4.83 g (98%), colourless oil

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.3 Hz); 1.26-1.36 (2H, m); 1.40-1.49 (2H, m); 1.55-1.66 (10H, m); 2.33-2.38 (4H, m); 2.53 (2H, t, J=6.9 Hz); 3.92 (4H, s).

LC-MS: m/z: [M+H]⁺=254.4, R_(t)=2.0 min.

Step 3: 2-Butyl-2-azaspiro[4.5]decan-8-one

A solution of 10-butyl-1,4-dioxa-10-azadispiro[4.2.4.2]tetradecane (4.83 g, 19.1 mmol) in 5% strength sulfuric acid (50 ml) was stirred for 18 h at room temperature. The reaction solution was then washed with diethyl ether (3×20 ml) in order to remove neutral substances present. The aqueous phase was then rendered alkaline (pH ˜9) with 4 N sodium hydroxide solution and extracted with methylene chloride (4×30 ml). The combined organic phases of the alkaline extraction were dried with sodium sulfate and concentrated i. vac.

Yield: 3.54 g (89%), yellow oil

¹H-NMR (CDCl₃): 0.92 (3H, t, J=6.9 Hz); 1.34 (2H, qd, J=14.3 and 7.2 Hz); 1.43-1.52 (2H, m); 1.76 (2H, t, J=6.9 Hz); 1.87 (2H, t, J=6.8 Hz); 2.31-2.38 (4H, m); 2.39-2.44 (2H, m); 2.49 (2H, s); 2.62 (2H, t, J=6.9 Hz).

Step 4: 2-Butyl-8-dimethylamino-2-azaspiro[4.5]decane-8-carbonitrile

4 N hydrochloric acid (4.23 ml) and then a solution of the crude product of 2-butyl-2-azaspiro[4.5]decan-8-one (3.54 g, 16.9 mmol) in methanol (20 ml) were added to a 40% strength aqueous dimethylamine solution (10.4 ml, 75.3 mmol), cooled to 0° C., and methanol (4.7 ml). Potassium cyanide (2.67 g, 40 mmol) was added to the mixture and the mixture was stirred for 18 h at room temperature. Water (75 ml) was then added to the reaction solution and the mixture was extracted with methylene chloride (6×15 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 4.27 g (96%), yellow oil

This is a diastereoisomer mixture.

¹H-NMR (CDCl₃): All the characteristic signals are present.

Step 5: [2-Butyl-8-(iminophenylmethyl)-2-azaspiro[4.5]dec-8-yl]-dimethylamine

A 1.8 M phenyllithium solution in di-n-butyl ether (4.2 ml, 7.6 mmol) was added dropwise to a solution of 2-butyl-8-dimethylamino-2-azaspiro[4.5]decane-8-carbonitrile (1.0 g, 3.8 mmol) in absolute tetrahydrofuran (40 ml) at 0° C. under argon and the mixture was then stirred for 3 h at room temperature. Water (10 ml) and sodium chloride solution (10 ml) were then added, the phases were separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 1.59 g (>100%, crude product)

The crude product was reacted further without prior purification.

¹H-NMR (DMSO-d₆): All the characteristic signals are present (two diastereoisomers).

LC-MS: m/z: [M+H]⁺=342.3, R_(t)=0.6 min.

Step 6: [3-Butyl-8-(dimethylamino)-3-azaspiro[4.5]decan-8-yl]-phenylmethanone (Example no. 180, polar diastereomer and Example no. 181, non-polar diastereomer)

A solution of the crude product of [2-butyl-8-(iminophenylmethyl)-2-azaspiro[4.5]dec-8-yl]-dimethylamine (1.57 g, max. 3.8 mmol) in tetrahydrofuran/water (1:1, ˜20 ml) was acidified with formic acid (5 ml) and stirred for 18 h at room temperature. The tetrahydrofuran was then concentrated i. vac. and the aqueous residue was extracted with ethyl acetate (3×10 ml). The combined acid, aqueous extracts were rendered alkaline with 1 N sodium hydroxide solution and extracted with methylene chloride (3×20 ml). The combined organic extracts of the alkaline extraction were dried with sodium sulfate and concentrated i. vac. The crude product was purified by means of flash chromatography (100 g, 20×4.0 cm) with chloroform/methanol (95:5) and 1% acetic acid. In order to obtain the free bases of the particular product batches, the fractions were in each case concentrated i. vac., the residues were taken up in 1 M potassium carbonate solution and the suspensions were extracted with methylene chloride (3×10 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Example No. 106 Polar Diastereoisomer

Yield: 250 mg (19%), yellow oil

¹H-NMR (CDCl₃): 0.88 (3H, t, J=7.3 Hz); 1.24-1.37 (4H, m); 1.39-1.54 (4H, m); 1.62-1.71 (4H, m); 2.03-2.09 (2H, m); 2.26 (2H, s); 2.31 (6H, s); 2.32-2.37 (2H, m); 2.57 (2H, t, J=6.8 Hz); 7.33-7.39 (2H, m); 7.43-7.49 (1H, m); 8.21-8.25 (2H, m).

LC-MS: m/z: [M+H]⁺=343.4, R_(t)=2.2 min.

Example No. 107 Non-Polar Diastereoisomer

Yield: 170 mg (13%), yellow oil

¹H-NMR (CDCl₃): 0.92 (3H, t, J=7.3 Hz); 1.27-1.38 (4H, m); 1.46-1.65 (8H, m); 2.06-2.12 (2H, m); 2.32 (6H, s); 2.47-2.52 (2H, m); 2.55 (s, 2H); 2.63 (2H, t, J=6.8 Hz); 7.34-7.39 (2H, m); 7.44-7.49 (1H, m); 8.20-8.24 (2H, m).

LC-MS: m/z: [M+H]⁺=343.4, R_(t)=2.2 min.

Example No. 117 8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one (Example no. 117, a diastereomer)

A suspension of 8-(dimethylamino)-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (1.76 g, 7.9 mmol) in absolute tetrahydrofuran (75 ml) was slowly added dropwise to a 0.5 M suspension of 5-chloro-2-thienylmagnesium bromide (5.29 g, 48 ml, 23.9 mmol) in tetrahydrofuran under argon, a clear solution being formed. The solution was then stirred overnight at 50° C. After addition of saturated ammonium chloride solution (100 ml) the tetrahydrofuran was removed i. vac. The aqueous solution obtained was extracted with methylene chloride (3×50 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac. The crude product (2.45 g) was purified by means of flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol (97:3).

Example No. 117 A Diastereoisomer

Yield: 1.47 g (59%), yellow solid.

Melting point: 198-201° C.

¹H-NMR (CDCl₃): 1.28-1.34 (2H, m); 1.61-1.68 (2H, m); 2.01 (2H, t, J=6.9 Hz); 2.12 (6H, s); 2.17 (2H, dt, J=13.1 and 3.1 Hz), 2.32-2.40 (2H, m); 3.28-3.32 (2H, m); 5.90 (1H, br s); 6.60 (1H, d, J=3.8 Hz); 6.83 (1H, d, J=3.8 Hz).

¹³C-NMR (CDCl₃): 27.9; 31.5; 32.7; 37.9; 38.7; 43.1; 58.9; 123.1; 125.2, 127.4; 144.4; 182.4.

LC-MS: m/z: [MH-HNMe₂]⁺=268.2, R_(t)=2.6 min.

Example No. 152 8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one (Example no 152, polar diastereomer)

Trifluoroacetic acid (5 ml) was added to a solution of 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-2-oxo-3-azaspiro[4.5]decane-3-carboxylic acid tert-butyl ester (polar diastereoisomer) (900 mg, 2.3 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated i. vac., methylene chloride (30 ml) was added to the residue and the mixture was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (622 mg) was purified by flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (14:1) and 0.5% ammonia (25% in water).

Example No. 152 Polar Diastereoisomer

Yield: 502 mg (75%), white solid

Melting point: 198-201° C.

¹H-NMR (CDCl₃): 1.46-1.54 (2H, m); 1.72-1.80 (2H, m); 1.85-2.10 (4H, m); 2.11 (6H, s); 2.25 (2H, s); 2.45 (3H, d, J=1.0 Hz); 3.07 (2H, s); 5.72 (1H, br s); 6.61 (1H, d, J=3.5 Hz); 6.66-6.69 (1H, m).

¹³C-NMR (CDCl₃): 15.2; 32.6; 32.8; 38.2; 38.9; 42.3; 53.7; 59.7; 124.5; 125.0; 137.9; 177.4.

LC-MS: m/z: [MH-HNMe₂]⁺=248.3 (100%) and [M+H]⁺=293.3 (10%), R_(t)=2.2 min.

Example No. 153 8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one (Example no. 153, non-polar diastereomer)

Trifluoroacetic acid (5 ml) was added to a solution of 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-2-oxo-3-azaspiro[4.5]decane-3-carboxylic acid tert-butyl ester (Example no. 251, non-polar diastereoisomer) (820 mg, 2.09 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated i. vac., methylene chloride (30 ml) was added to the residue and the mixture was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated I. vac. The crude product (530 mg) was purified by flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 153 Non-Polar Diastereoisomer

Yield: 425 mg (70%), white solid

¹H-NMR (CDCl₃): 1.46-1.56 (2H, m); 1.74-1.84 (2H, m); 1.86-2.09 (4H, m); 2.11 (6H, s); 2.115 (2H, s); 2.47 (3H, d, J=1.1 Hz); 3.22 (2H, s); 5.78 (1H, br s); 6.61 (1H, d, J=3.5 Hz); 6.67-6.69 (1H, m).

¹³C-NMR (CDCl₃): 15.2; 32.6; 38.1; 38.8; 43.2; 52.7; 59.4; 124.5; 124.9; 137.9; 140.0; 177.4.

LC-MS: m/z: [M+H]⁺=293.3, R_(t)=2.2 min.

Example No. 162 Step 1: 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one

A suspension of 8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-8-carbonitrile (536 mg, 2.4 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise to a 2 M solution of phenylmagnesium chloride in tetrahydrofuran (3 ml, 6 mmol), cooled to 0° C., under argon and the mixture was then stirred for 18 h at room temperature. After addition of saturated ammonium chloride solution (15 ml) the phases were separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 601 mg (92 white solid (crude product)

Diastereoisomer mixture: Polar:non-polar ratio=1:2.

The diastereoisomer ratio was determined with the aid of the singlets of the HN—CH₂ group at 3.27 (polar diastereoisomer) and 3.02 ppm (non-polar diastereoisomer) in the ¹H-NMR spectrum.

Step 2: 8-Dimethylamino-3-oxo-8-phenyl-2-azaspiro[4.5]decan-2-carboxylic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (4.05 g, 18.6 mmol) in anhydrous tetrahydrofuran (30 ml) and 4-dimethylaminopyridine (206 mg, 1.69 mmol) was added to a solution of 8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (4.60 g, 16.9 mmol) in anhydrous acetonitrile (300 ml) and anhydrous tetrahydrofuran (100 ml) and the mixture was stirred for 3 d at room temperature. Since the reaction was not complete, a solution of di-tert-butyl dicarbonate (2.00 g, 9 mmol) in anhydrous acetonitrile (10 ml) was again added and the mixture was stirred for 3 h at 50° C. and for 18 h at room temperature. The solvent was then removed i. vac., the residue was dissolved in methylene chloride (100 ml) and the solution was washed with water (3×50 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (7.00 g) was purified by flash chromatography (400 g, 20×7.5 cm) with ethyl acetate/methanol (9:1).

Non-Polar Diastereoisomer

Yield: 1.40 g (22%), white solid

Melting point: 174-176° C.

¹H-NMR (CDCl₃): 1.34-1.42 (2H, m); 1.53 (9H, s); 1.72-1.82 (2H, m); 1.96-2.03 (2H, m); 2.04 (6H, s); 2.10-2.24 (2H, m); 2.25 (2H, s); 3.61 (2H, s); 7.26-7.31 (3H, m); 7.36-7.41 (2H, m).

¹³C-NMR (CDCl₃): 28.1; 30.0; 32.2; 34.3; 38.0; 45.8; 56.6; 60.1; 82.8; 126.8; 127.4; 127.8; 150.1; 173.4.

LC-MS: m/z: [M+H]⁺=373.4, R_(t)=2.6 min.

Polar Diastereoisomer

Yield: 1.26 g (20%), white solid

Melting point: 176-181° C.

¹H-NMR (CDCl₃): 1.34-1.44 (2H, m); 1.48 (9H, s); 1.68-1.77 (2H, m); 1.90-2.03 (2H, m); 2.04 (6H, s); 2.15-2.30 (2H, m); 2.48 (2H, s); 3.36 (2H, s); 7.28-7.32 (3H, m); 7.36-7.42 (2H, m).

¹³C-NMR (CDCl₃): 28.0; 29.8; 32.3; 34.5; 38.0; 44.9; 57.6; 60.3; 60.5; 82.7; 126.8; 127.5; 127.8; 136.2; 150.1; 173.4.

LC-MS: m/z: [M+H]⁺=373.4, R_(t)=3.0 min.

Step 3: 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (non-polar diastereomer)

Trifluoroacetic acid (5 ml) was added to a solution of 8-dimethylamino-3-oxo-8-phenyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (non-polar diastereoisomer) (1.46 g, 3.9 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated i. vac., the residue was dissolved in methylene chloride (50 ml) and the solution was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Yield: 1.03 g (96%), white solid

Melting point: >260° C.

¹H-NMR (CDCl₃): 1.37-1.46 (2H, m); 1.76-1.84 (2H, m); 1.90-2.02 (2H, br s); 2.04 (6H, s); 2.06 (2H, s); 2.15-2.27 (2H, br s); 3.27 (2H, s); 5.60 (1H, s); 7.26-7.32 (3H, m); 7.36-7.42 (2H, m).

Step 4: 8-(Dimethylamino)-3-methyl-8-phenyl-3-azaspiro[4.5]decan-2-on (Example no. 162, non-polar diastereomer)

Potassium tert-butylate (74 mg, 0.66 mmol) was added to a suspension of 8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (non-polar diastereomer) (150 mg, 0.55 mmol) in anhydrous tetrahydrofuran (20 ml) and anhydrous N,N-dimethylformamide (3 ml) and the mixture was stirred for 30 min at room temperature. Methyl iodide (94 mg, 41 μl, 0.66 mmol) was then added and the mixture was stirred for 5 h at room temperature. The solution was then concentrated i. vac. After addition of ethyl acetate (50 ml) the mixture was washed with water (3×20 ml). The organic phase was then extracted with 5% strength formic acid (3×20 ml). The combined aqueous, acid phases were adjusted to pH 10 with 5 N sodium hydroxide solution and extracted with ethyl acetate (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated vac.

Example No. 162 Non-Polar Diastereoisomer

Yield: 120 mg (76%), white solid

Melting point: 145-148° C.

¹H-NMR (CDCl₃): 1.33-1.42 (2M, m); 1.70-1.78 (2H, m); 1.85-2.02 (2H, m); 2.03 (6H, s); 2.12 (2H, s); 2.13-2.25 (2H, m); 2.83 (3H, s); 3.34 (2H, s); 7.24-7.31 (3H, m); 7.35-7.41 (2H, m).

¹³C-NMR (CDCl₃): 29.7; 30.2; 33.1; 35.5; 38.0; 44.2; 60.1; 60.5; 126.7; 127.4; 127.7; 173.8. LC-MS: m/z: [M+H]⁺=287.4, R_(t)=1.3 min.

Example No. 186 Step 1: 2-[3-(tert-Butyldimethylsilanyloxy)-3-methylbutyl]-8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one

A suspension of powdered sodium hydroxide dried i vac. (106 mg, 2.64 mmol) in absolute dimethylsulfoxide (5 ml) was stirred for 40 min at room temperature. 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (Example no. 152, step 3, non-polar diastereomer) (180 mg, 0.66 mmol) was then added to this, before a solution of 3-(tert-butyldimethylsilyloxy)-3-methylbutyl 4-methylbenzenesulfonate (272 mg, 0.73 mmol) in dimethylsulfoxide (2 ml) was added, and the mixture was stirred for 2 h at room temperature. A solution of 3-(tert-butyldimethylsilyloxy)-3-methylbutyl 4-methylbenzenesulfonate (136 mg, 0.37 mmol) in dimethylsulfoxide (2 ml) was then again added and the mixture was stirred for 18 h at room temperature. Water (100 ml) was then added to the mixture and the mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was repeatedly taken up in toluene (3×10 ml) and the mixture was each time concentrated again i. vac.

The crude product (420 mg, >100%) was reacted further without prior purification.

Step 2: 8-Dimethylamino-2-(3-hydroxy-3-methylbutyl)-8-phenyl-2-azaspiro[4.5]decan-3-one (Example no. 186, non-polar diastereomer)

2 N hydrochloric acid (7.5 ml) was added to a solution of the crude product of 2-[3-(tert-butyldimethylsilanyloxy)-3-methylbutyl]-8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (non-polar diastereomer) (420 mg, max. 0.66 mmol) in methanol (20 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was rendered alkaline with 1 M potassium carbonate solution and the methanol was removed i. vac. The aqueous residue was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product was purified by means of flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (4:1).

Example No. 186 Non-Polar Diastereoisomer

Yield: 105 mg (44%), white solid

Melting point: 114-119° C.

¹H-NMR (CDCl₃): 1.25 (6H, s); 1.30-1.41 (2H, m); 1.63-1.68 (2H, m); 1.69-1.79 (2H, m); 1.91-2.03 (2H, m); 2.02 (6H, s); 2.12 (2H, s); 2.13-2.24 (4H, m); 2.28-2.45 (1H, br s); 3.27 (2H, s); 3.37-3.42 (2H, m); 7.25-7.30 (3H, m); 7.35-7.40 (2H, m).

¹³C-NMR (CDCl₃): 29.6; 30.2; 32.8; 35.8; 38.0; 38.8; 40.1; 44.5; 58.3; 60.1; 69.5; 126.7; 127.4; 127.7; 136.4; 174.0.

LC-MS: m/z: [MH-HNMe₂]⁺=314.3 (82%) and [M+H]⁺=359.3 (100%), R_(t)=2.3 min.

Example No. 187 Step 1: 2-[3-(tert-Butyldimethylsilanyloxy)-3-methylbutyl]-8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one

A suspension of powdered sodium hydroxide dried i. vac. (106 mg, 2.64 mmol) in absolute dimethylsulfoxide (5 ml) was stirred for 40 min at room temperature. 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (180 mg, 0.66 mmol) was then added to this and a solution of 3-(tert-butyldimethylsilyloxy)-3-methylbutyl 4-methylbenzenesulfonate (272 mg, 0.73 mmol) in dimethylsulfoxide (2 ml) was added. After 2 h at room temperature a solution of 3-(tert-butyldimethylsilyloxy)-3-methylbutyl 4-methylbenzenesulfonate (136 mg, 0.37 mmol) in dimethylsulfoxide (2 ml) was again added and the mixture was stirred for 18 h at room temperature. Water (100 ml) was then added to the mixture and the mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue was repeatedly taken up in toluene (3×10 ml) and the mixture was each time concentrated again i. vac.

The crude product (450 mg, >100%) was reacted further without prior purification.

Step 2: 8-Dimethylamino-2-(3-hydroxy-3-methylbutyl)-8-phenyl-2-azaspiro[4.5]decan-3-one (Example no. 187, polar diastereomer)

2 N hydrochloric acid (7.5 ml) was added to a solution of the crude product of 2-[3-(tert-butyldimethylsilanyloxy)-3-methylbutyl]-8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (polar diastereomer) (450 mg, max. 0.66 mmol) in methanol (20 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was then rendered alkaline with 1 M potassium carbonate solution and the methanol was removed i. vac. The aqueous residue was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product was purified by means of flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (4:1). The product batch (150 mg) obtained by this procedure contained 3-methyl-1,3-butanediol as an impurity and was purified again by means of flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (9:1).

Example No. 187 Polar Diastereoisomer

Yield: 120 mg (51%), colourless oil

¹H-NMR (CDCl₃): 1.21 (6H, s); 1.32-1.40 (2H, m); 1.56-1.61 (2H, m); 1.67-1.74 (2H, m); 1.88-2.00 (2H, m); 2.02 (6H, s); 2.15-2.29 (2H, m); 2.34 (2H, s); 3.02 (2H, s); 3.31-3.36 (2H, m); 7.24-7.30 (3H, m); 7.35-7.40 (2H, m).

¹³C-NMR (CDCl₃): 29.5; 30.0; 33.0; 35.9; 38.0; 38.6; 40.0; 43.6; 59.2; 60.7; 69.5; 126.7; 127.6; 127.8; 136.2; 174.0.

LC-MS: m/z: [MH-HNMe₂]⁺=314.3 (100%) and [M+H]⁺=359.4 (55%), R_(t)=2.6 min.

Example No. 213 Step 1: 3-(8-Dimethylamino-8-thiophen-2-yl-2-azaspiro[4.5]dec-2-yl)propionic acid methyl ester

Methyl acetate (2.00 g, 2.16 ml, 24 mmol) was added to a solution of Example no. 21 (320 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 ml) and the mixture was stirred for 3 d at 150° C. The reaction mixture was then concentrated i. vac. and the residue (365 mg) was purified by flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (95:5) and 0.5% ammonia (25% in water).

Yield: 274 mg (65%), colourless oil

¹H-NMR (CDCl₃): 1.33-1.41 (2H, m); 1.51 (2H, t, J=6.8 Hz); 1.65-1.74 (2H, m); 1.87-2.00 (2H, m); 2.10 (8H, s); 2.44 (2H, s); 2.47-2.56 (4H, m); 2.70-2.75 (2H, m); 3.68 (3H, s); 6.85 (1H, d, J=3.0 Hz); 7.03 (1H, dd, J=5.1 and 3.5 Hz); 7.23 (1H, br d, J=4.8 Hz).

Step 2: 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-ethylpentan-3-ol (Example no. 213, polar diastereomer)

Titanium tetra-isopropylate (45 mg, 48 μl, 0.16 mmol) was added to a solution of 3-(8-dimethylamino-8-thiophen-2-yl-2-azaspiro[4.5]dec-2-yl)propionic acid methyl ester (274 mg, 0.78 mmol) in anhydrous tetrahydrofuran (5 ml) under argon. A 0.3 M solution of ethylmagnesium bromide (7.8 ml, 2.34 mmol) in diethyl ether was then slowly added dropwise in the course of 1 h and the mixture was stirred overnight at room temperature. 5% strength aqueous sulfuric acid (5 ml) was added to the honey-yellow solution and the mixture was stirred vigorously. pH 10 was established by addition of 2 M potassium carbonate solution and the mixture was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (250 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Example No. 213 Polar Diastereoisomer

Yield: 85 mg (29%), oil

¹H-NMR (CDCl₃): 0.84 (6H, t, J=7.5 Hz); 1.31-1.58 (10H, m); 1.64-1.74 (2H, m); 1.88-1.98 (2H, m); 2.00-2.09 (2H, m); 2.10 (6H, s); 2.48 (2H, s); 2.58 (2H, t, J=7.0 Hz); 2.64-2.69 (2H, m); 6.25 (1H, br s); 6.83 (1H, dd, J=3.5 and 1.1 Hz); 7.02 (1H, dd, J=5.1 and 3.5 Hz); 7.21 (1H, dd, J=5.1 and 1.1 Hz).

¹³C-NMR (CDCl₃): 8.1; 26.9; 30.9; 33.5; 33.9; 37.2; 38.1; 40.9; 52.2; 53.5; 59.6; 65.5; 74.9; 123.2; 124.8; 126.1; 143.1.

LC-MS: m/z: [M+H]⁺=379.4, R_(t)=1.9 min.

Example No. 214 Step 1: 8-Dimethylamino-8-thiophen-2-ylmethyl-2-azaspiro[4.5]decan-1-one

Lithium chloride (269 mg, 6.33 mmol) was heated by means of a hot air gun in a Schlenk flask under a high vacuum for 10 min. Magnesium (220 mg, 9.05 mmol) was then added and the mixture was heated once more for 10 min by means of a hot air gun under a high vacuum. Absolute tetrahydrofuran (1.5 ml) freshly distilled over calcium hydride and one drop of a 25% strength diisobutylaluminum hydride solution in toluene were then added and the mixture was stirred for 5 min at room temperature. Substance F (equation 1, R₁=R₂=methyl) (400 mg, 1.18 mmol) was then added and a solution, dried for 40 min over a molecular sieve of 4 Å, of 2-(bromomethyl)thiophene (1.18 g, 6.66 mmol) in absolute tetrahydrofuran (2 ml) freshly distilled over calcium hydride was slowly added dropwise to this suspension, warming of the solution and dissolving of the starting substance being observed. The reaction mixture was stirred for 30 min at room temperature and then for 3 h at 55° C. Thereafter saturated ammonium chloride solution (6 ml) was slowly added and the mixture was stirred for 16 h at room temperature. After addition of 2 M sodium hydroxide solution (8 ml) and water (30 ml) the mixture was extracted with ethyl acetate (2×100 ml) and chloroform/methanol (7:1, 50 ml), the combined organic phases were washed with saturated sodium chloride solution (30 ml) and dried with magnesium sulfate and the solvent was removed i. vac. The residue (706 mg) was taken up in diethyl ether (20 ml), the suspension was filtered, the residue on the filter was washed with diethyl ether and the filtrate was concentrated i. vac. This residue was purified by flash chromatography (18 g, 20×2 cm) with ethyl acetate/methanol (2:0.1→2:0.4) and 1% ammonia (25% in water).

Non-Polar Diastereoisomer

Yield: 240 mg (45%), colourless oil.

¹H-NMR (CDCl₃): 1.15 (2H, d, J=13.1 Hz); 1.32 (2H, t, J=14.1 Hz); 1.74-1.87 (4H, m); 2.02-2.12 (2H, m); 2.29 (6H, s); 2.85 (2H, s); 3.21 (2H, t, J=7.1 Hz); 6.16 (1H, s); 6.75 (1H, d, J=2.8 Hz); 6.92 (1H, dd, J=5.2 and 3.4 Hz); 7.12 (1H, dd, J=5.2 and 1.2 Hz).

LC-MS: [M+H]⁺: m/z=293.3, R_(t)=2.2 min.

Polar Diastereoisomer

Yield: 20 mg (3.8%), colourless oil.

¹H-NMR (CDCl₃): 1.46-1.63 (4H, m); 1.70-1.85 (4H, m), 2.00 (2H, t, J=6.9 Hz); 2.31 (6H, s); 3.10 (2H, s); 3.28 (2H, t, J=6.9 Hz); 6.25 (1H, s); 6.86 (1H, dd, J=3.4 Hz); 6.90 (1H, dd, J=5.1 Hz); 7.13 (1H, dd, J=5.1 Hz).

LC-MS: [M+H]⁺: m/z=293.3, R_(t)=0.6 min.

Step 2: N,N-Dimethyl-8-(thiophen-2-ylmethyl)-2-azaspiro[4.5]decan-8-amine (non-polar diastereomer)

8-Dimethylamino-8-thiophen-2-ylmethyl-2-azaspiro[4.5]decan-1-one (non-polar diastereomer) (230 mg, 0.79 mmol), dissolved in absolute tetrahydrofuran (6 ml) was slowly added to a suspension of lithium aluminium hydride (150 mg, 3.95 mmol) in absolute tetrahydrofuran (5 ml) in a Schlenk flask under argon at 0° C. The ice bath was then removed and the mixture was stirred for 16 h at 50° C. Water (150 μl), 15% strength sodium hydroxide solution (150 μl), tetrahydrofuran (10 ml) and water (450 μl) were then added successively at 0° C. and the suspension was stirred for 1 h at room temperature. The suspension was filtered through sodium sulfate, the residue was washed with methylene chloride (2×30 ml) and the filtrate was concentrated to dryness i. vac.

Yield: 207 mg (95%), yellow oil.

¹H-NMR (CDCl₃): 1.20-1.28 (2H, m); 1.33-1.45 (4H, m); 1.60-1.71 (4H, m); 2.28 (6H, s); 2.65 (2H, s); 2.87-2.93 (4H, m); 6.76 (1H, dd, J=3.4 and 1.1 Hz); 6.92 (1H, dd, J=5.2 and 3.4 Hz); 7.12 (1H, dd, J=5.2 and 1.2 Hz).

LC-MS: [M+H]⁺: m/z=279.3, R_(t)=0.2 min.

Step 3: 1-(8-Dimethylamino-8-thiophen-2-ylmethyl-2-azaspiro[4.5]dec-2-yl)-butan-1-one (Example no, 214, non-polar diastereomer)

First triethylamine (116 mg, 160 μl, 1.14 mmol) and then slowly butyryl chloride (99 mg, 96 μl, 0.93 mmol) were added to a solution of N,N-dimethyl-8-(thiophen-2-ylmethyl)-2-azaspiro[4.5]decan-8-amine (non-polar diastereomer) (199 mg, 0.72 mmol) in absolute methylene chloride (5 ml) in a 10 ml Schlenk flask under argon at room temperature. The reaction mixture was stirred for 16 h at room temperature and saturated sodium carbonate solution (20 ml) was then added. After addition of methylene chloride (10 ml) the phases were separated and the aqueous phase was extracted with methylene chloride (2×25 ml). The combined organic phases were washed successively with saturated sodium carbonate solution (20 ml), 0.2 M sodium hydroxide solution (10 ml) and saturated sodium chloride solution (10 ml) and dried with magnesium sulfate and the solvent was removed i. vac. The crude product (264 mg) was purified first by flash chromatography (PuriFlash PF-15SIHP, 8 g) with methylene chloride/methanol 95:5→80:20) and 1% ammonia (25% in water) and then again by flash chromatography (7 g, 20×1.5 cm) with methylene chloride/methanol (95:5→80:20) and 1% ammonia (25% in water).

Example No. 217 Non-Polar Diastereoisomer

Yield: 161 mg (65%), yellow solid.

Melting point: 86° C.

1H-NMR (CDCl3): 0.94 (3H, t, J=7.4 Hz); 1.21-1.47 (4H, m); 1.56 (1H, t, J=7.3 Hz); 1.60-1.77 (7H, m); 2.18 (2H, t, J=7.5 Hz); 2.27 and 2.28 (6H, s); 2.88 and 2.90 (2H, 2 s); 3.16 (1H, s); 3.24 (1H, s); 3.38-3.46 (2H, m); 6.80-6.73 (1H, m); 6.91-6.94 (1H, m); 7.13 (1H, d, J=5.1 Hz). Some signals are to be seen as a doubled signal set (rotamers).

¹³C-NMR (CDCl₃): 13.99; 14.01; 18.3; 18.4; 28.5; 29.0; 29.8; 30.1; 31.1; 31.3; 32.7; 34.9; 36.3; 36.7; 37.1; 37.1; 40.1; 42.0; 44.2; 45.3; 57.36; 57.38; 59.4; 123.9; 124.0; 126.3; 126.5; 126.45; 126.60; 126.7; 141.0; 141.2; 171.7; 171.8.

LC-MS: [M+H]⁺: m/z=349.3, R_(t)=2.8 min.

Example No. 234 Step 1: Cyclopent-1-enemagnesium bromide

Magnesium (1.70 g, 70 mmol) and an iodine crystal were heated in a secure apparatus such that iodine gas was formed. The mixture was cooled to room temperature and anhydrous tetrahydrofuran (17 ml) and a further iodine crystal were then added. A solution of 1-bromocyclopentene (10.3 g, 70 mmol) in anhydrous tetrahydrofuran (23 ml) was then added dropwise such that the reaction mixture started to boil. The mixture was stirred for a further 1 h under reflux and then cooled to room temperature. The solution obtained in this way was employed in the next step.

Step 2: (8-Cyclopent-1-enyl-1,4-dioxaspiro[4.5]dec-8-yl)-dimethylamine

A solution of 8-(dimethylamino)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (6.05 g, 28.7 mmol) in anhydrous tetrahydrofuran (40 ml) was added dropwise to the solution from step 1 (max. 70 mmol). The mixture was stirred overnight at room temperature and then for 2 h at 60° C. and thereafter saturated ammonium chloride solution (50 ml) and water (50 ml) were added, while cooling with ice. The pH of the mixture was adjusted to 9 with 4 N sodium hydroxide solution. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product was purified by flash chromatography (400 g, 20×7.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Yield: 2.54 g (35%), yellow oil

¹H-NMR (CDCl₃): 1.50-1.60 (2H, m); 1.70-1.94 (8H, m); 2.20 (6H, s); 2.24-2.30 (2H, m); 2.31-2.39 (2H, m); 3.88-3.96 (4H, m); 5.53 (1H, m).

¹³C-NMR (CDCl₃): 23.6; 29.0; 31.4; 32.2; 33.1; 38.5; 58.4; 64.1; 109.0; 128.2; 143.8.

LC-MS: [M+H]⁺: m/z=252.3, R_(t)=1.9 min.

Step 3: (8-Cyclopentyl-1,4-dioxaspiro[4.5]dec-8-yl)-dimethylamine

5% rhodium on activated aluminium oxide (2.05 g, 1 mmol) was added to a solution of (8-cyclopent-1-enyl-1,4-dioxaspiro[4.5]dec-8-yl)-dimethylamine (2.53 g, 10 mmol) in anhydrous methanol (220 ml). The suspension was stirred for 18 h at 50° C. and under a hydrogen pressure of 4 bar and then filtered through Celite which had been washed with methanol beforehand. The filtrate was concentrated i. vac.

Yield: 2.51 g (100%), yellow oil

¹H-NMR (CDCl₃): 1.20-1.34 (2H, m); 1.38-1.64 (10H, m); 1.68-1.78 (2H, m); 1.82-1.94 (2H, m); 2.07 (1H, m); 2.27 (6H, s); 3.91-3.94 (4H, m).

¹³C-NMR (CDCl₃): 25.0; 28.0; 28.5; 30.0; 37.8; 43.8; 57.5; 64.1; 109.6.

Step 4: 4-Cyclopentyl-4-dimethylaminocyclohexanone

A solution of (8-cyclopentyl-1,4-dioxaspiro[4.5]dec-8-yl)-dimethylamine (5.21 g, 20.5 mmol) in 1 M aqueous sulfuric acid (150 ml) was stirred for 48 h at room temperature. The mixture was washed with methylene chloride (2×70 ml). The aqueous phase was rendered alkaline with 4 N sodium hydroxide solution and extracted with methylene chloride (4×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 3.52 g (82%), yellow oil

¹H-NMR (CDCl₃): 1.18-1.34 (2H, m); 1.40-1.80 (8H, m); 1.96-2.08 (2H, m); 2.10-2.22 (3H, m); 2.34 (6H, s); 2.51-2.63 (2H, m).

¹³C-NMR (CDCl₃): 24.9; 28.6; 30.1; 36.6; 37.2; 38.0; 43.4; 57.5.

The carbonyl carbon was detected by a gHMBC spectrum at 212 ppm.

LC-MS: [M+H]⁺: m/z=210.3, R_(t)=0.8 min.

Step 5: (4-Cyclopentyl-4-dimethylaminocyclohexylidene)-acetic acid ethyl ester

Potassium tert-butanolate (2.99 g, 26.7 mmol) was added to a solution of phosphonoacetic acid triethyl ester (6.74 g, 5.98 ml, 30.1 mmol) in anhydrous N,N-dimethylformamide (30 ml) and the mixture was stirred for 1 h at 50° C. The solution was cooled to room temperature and a solution of 4-cyclopentyl-4-dimethylaminocyclohexanone (3.96 g, 18.9 mmol) in anhydrous N,N-dimethylformamide (50 ml) was then added. The reaction mixture was stirred for 20 h at room temperature and then poured into ice-water (75 g). The suspension was extracted with diethyl ether (4×40 ml). These combined organic phases were dried with sodium sulfate and concentrated i. vac. Toluene was first repeatedly added to the residue and the mixture concentrated i. vac. again each time and thereafter the procedure was repeated with cyclohexane. This residue (5.49 g) was taken up in ethyl acetate (30 ml) and the solution was extracted with 10% strength formic acid (5×30 ml). The combined acid, aqueous phases were rendered alkaline with 4 N sodium hydroxide solution and extracted with methylene chloride (5×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 4.36 g (77%), colourless oil

¹H-NMR (CDCl₃): 1.14-1.70 (13H, m); 1.78-2.40 (5H, m); 2.32 (6H, s); 2.57 (1H, br t, J=13.9 Hz); 3.55 (1H, br d, J=12.6 Hz); 4.13 (2H, q, J=7.0 Hz); 5.58 (1H, s).

Step 6: (4-Cyclopentyl-4-dimethylamino-1-nitromethylcyclohexyl)-acetic acid ethyl ester

Nitromethane (1.22 ml, 1.07 ml, 20 mmol) was added to a mixture of (4-cyclopentyl-4-dimethylaminocyclohexylidene)acetic acid ethyl ester (4.35 g, 15.6 mmol) and tetra-n-butylammonium fluoride trihydrate (5.36 g, 17 mmol) in anhydrous tetrahydrofuran (37 ml). The solution was stirred for 7.5 h at 70° C. and then for 18 h at 45° C. The mixture was concentrated i. vac. The residue (9.9 g) was purified by flash chromatography (400 g, 20×7.5 cm) with cyclohexane/ethyl acetate (1:4).

Yield: 3.04 g (57%), yellowish oil.

¹H-NMR (CDCl₃): 1.26 (0.3 H, t, J=7.0 Hz); 1.27 (2.7 H, t, J=7.1 Hz); 1.30-1.75 (16H, m); 2.06 (1H, m); 2.24 (6H, s); 2.46 (0.2 H, s); 2.59 (1.8 H, s); 4.15 (2H, q, J=7.1 Hz); 4.58 (1.8 H, s); 4.81 (0.2 H, s)

¹³C-NMR (CDCl₃): 14.2; 25.05; 24.14; 25.4; 28.1; 28.45; 28.50; 35.0; 36.8; 37.7; 43.6; 44.0; 44.1; 57.4; 60.1; 60.2; 84.3; 171.3.

This is a diastereoisomer mixture.

Step 7: 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one

A 50% strength aqueous Raney nickel suspension (1.15 ml) was added to a solution of (4-cyclopentyl-4-dimethylamino-1-nitromethylcyclohexyl)-acetic acid ethyl ester (3.04 g) in methanol (50 ml). The suspension was stirred for 5 h at 60° C. and under a hydrogen pressure of 5 bar. The suspension was filtered through Celite, the residue on the filter was washed with methanol (2×10 ml) and the filtrate was concentrated i. vac.

Yield: 2.36 g (100%), white solid

¹H-NMR (CDCl₃): 1.16-1.80 (16H, m); 2.05 (1H, m); 2.12 (0.3 H, s); 2.20 (1.7 H, s); 2.26 (6H, s); 3.09 (1.7 H, s); 3.18 (0.3 H, s); 6.04 (1H, br s).

This is a diastereoisomer mixture in the ratio of approx. 7:1.

Step 8: 8-Cyclopentyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decan-2-carboxylic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (2.14 g, 9.83 mmol) in anhydrous acetonitrile (20 ml) and 4-dimethylaminopyridine (69 mg, 0.87 mmol) was added to a solution of 8-cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (2.36 g, 8.92 mmol) in anhydrous acetonitrile (60 ml) and the mixture was then stirred overnight at 50° C. Since the conversion (¹H-NMR) was not complete, further di-tert-butyl carbonate (2.14 g, 9.83 mmol) was added and the mixture was stirred for a further 18 h at 50° C. The mixture was concentrated I. vac. and the residue was taken up in methylene chloride (100 ml). The solution was washed with water (3×80 ml) and saturated sodium chloride solution (2×50 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (3.54 g) was purified by flash chromatography (200 g, 20×5.7 cm) with methylene chloride/methanol (98:2-95:5). Yield:

Nonpolar Diastereoisomer

Yield: 1.74 g (53%), yellowish solid

¹H-NMR (CDCl₃): 1.16-1.36 (6H, m); 1.38-1.63 (6H, m); 1.51 (9H, s); 1.64-1.80 (4H, m); 2.05 (1H, m); 2.26 (6H, s); 2.40 (2H, s); 3.44 (2H, s).

Polar Diastereoisomer

Yield: 408 mg (12%), yellow oil

¹H-NMR (CDCl₃): 1.10-1.85 (25H, m); 2.06 (1H, m); 2.25 (6H, s); 2.32 (2H, s); 3.54 (2H, s).

Step 9: 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer)

Trifluoroacetic acid (10 ml) was added to a solution of 8-cyclopentyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester—non-polar diastereoisomer (1.74 g, 4.77 mmol) in anhydrous methylene chloride (75 ml) and the mixture was stirred overnight at room temperature. The mixture was concentrated i. vac., the residue was taken up in methylene chloride (150 ml) and the solution was washed with saturated sodium bicarbonate solution (3×50 ml). The aqueous phase was extracted with a methylene chloride/isopropanol mixture (4:1, 3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 1.08 g (86%), white solid

¹H-NMR (CDCl₃): 1.16-1.82 (16H, m); 2.06 (1H, m); 2.21 (2H, s); 2.26 (6H, s); 3.10 (2H, s); 5.86 (1H, br s).

Step 10: 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (polar diastereoisomer)

Trifluoroacetic acid (3.38 ml) was added to a solution of 8-cyclopentyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tart-butyl ester—polar diastereoisomer (446 mg, max. 1.22 mmol, contaminated) in anhydrous methylene chloride (35 ml) and the mixture was stirred for 4 h at room temperature. The mixture was concentrated i. vac., the residue was taken up in methylene chloride (40 ml) and the solution was washed with saturated sodium bicarbonate solution (3×30 ml). The aqueous phase was extracted with a methylene chloride/isopropanol mixture (4:1, 3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (326 mg) was purified by flash chromatography (38 g, 20×2.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Yield: 176 mg (54%), white solid

¹H-NMR (CDCl₃): 1.16-1.32 (4H, m); 1.36-1.62 (8H, m); 1.63-1.82 (4H, m); 2.06 (1H, m); 2.14 (2H, s); 2.26 (6H, s); 3.20 (2H, s); 5.81 (1H, br s).

Step 11: 8-Cyclopentyl-3-(2-cyclopropyl-ethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one (Example no. 234, non-polar diastereoisomer)

A suspension of sodium hydroxide (96 mg, 2.39 mmol) in anhydrous dimethylsulfoxide (5 ml) was stirred for 40 min at room temperature, 8-cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer) (158 mg, 0.6 mmol) and subsequently a solution of 2-cyclopropylethyl 4-methylbenzenesulfonate (144 mg, 0.6 mmol) in anhydrous dimethylsulfoxide (2 ml) were then added and the mixture was stirred for 4 h at room temperature. A solution of 2-cyclopropylethyl 4-methylbenzenesulfonate (72 mg, 0.3 mmol) in anhydrous dimethylsulfoxide (2 ml) was again added to the reaction mixture and the mixture was stirred for a further 18 h at room temperature. Water (150 ml) was added to the mixture and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (300 mg) was purified by flash chromatography (18 g, 20×2.0 cm) with methylene chloride/methanol (98:2). 60 mg of the target compound were obtained in a pure form by this procedure. The contaminated product (90 mg) obtained by flash chromatography was taken up in ethyl acetate (10 ml) and the solution was extracted with 10% strength aqueous formic acid (4×20 ml). The combined acid, aqueous phases were rendered alkaline with 4 N sodium hydroxide solution and extracted with methylene chloride (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Example No. 234 Non-Polar Diastereoisomer

Yield: 131 mg (66%), yellowish oil

¹H-NMR (CDCl₃): 0.00-0.05 (2H, m); 0.38-0.45 (2H, m); 0.61 (1H, m); 1.10-1.80 (18H, m); 2.03 (1H, m); 2.24 (6H, s), 2.25 (2H, s); 3.08 (2H, s); 3.29 (2H, t, J=7.2 Hz).

¹³C-NMR (CDCl₃): 4.2; 8.5; 25.1; 25.4; 25.8; 26.0; 26.9; 28.5; 31.6; 32.3; 32.4; 36.3; 37.8; 42.4; 42.5; 44.2; 57.7; 61.1; 173.7.

LC-MS: [M+H]⁺: m/z=333.4, R_(t)=2.6 min.

Example No. 272 Step 1: 3-(8-Dimethylamino-8-phenyl-2-azaspiro[4.5]dec-2-yl)propionic acid methyl ester

Methyl acrylate (4.18 g, 4.20 ml, 46 mmol) was added to a solution of N,N-dimethyl-8-phenyl-2-azaspiro[4.5]decan-8-amine (600 mg, 2.32 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred for 18 h at 50° C. The reaction mixture was concentrated in vacuo and the residue (767 mg) was purified by flash chromatography (38 g, 20×2.5 cm) with methylene chloride/methanol (95:5) and 0.5% ammonia (25% in water).

Step 2: 4-(8-Dimethylamino-8-phenyl-2-azaspiro[4.5]dec-2-yl)-2-methylbutan-2-ol (Example no. 272)

A 1.4 M solution of methylmagnesium bromide (1.26 ml, 1.76 mmol) in toluene/tetrahydrofuran (3:1) was added to a solution of 3-(8-dimethylamino-8-phenyl-2-azaspiro[4.5]dec-2-yl)propionic acid methyl-ester (150 mg, 0.44 mmol) in anhydrous tetrahydrofuran (5 ml) under argon and the mixture was stirred overnight at room temperature. 5% strength aqueous sulfuric acid (5 ml) was added to the solution and the mixture was stirred vigorously. pH 10 was established by addition of 2 M potassium carbonate solution and the mixture was extracted with methylene chloride (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (130 mg) was taken up in ethyl acetate (30 ml) and the solution was then extracted with 5% strength aqueous formic acid (3×20 ml). The combined aqueous, acid phases were adjusted to pH 10 with 5 M sodium hydroxide solution and extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Analytical data of Example 272:

¹H-NMR (CDCl₃): 1.22 (6H, s); 1.23-1.30 (2H, m); 1.44 (2H, t, J=7.1 Hz); 1.56-1.60 (2H, m); 1.60-1.70 (2H, m); 1.80-1.97 (2H, m); 2.01 (6H, s); 2.10-2.26 (2H, m); 2.52 (2H, s); 2.57 (2H, t, J=7.1 Hz); 2.70-2.75 (2H, m); 6.10-6.80 (1H, br s); 7.22-7.30 (3H, m); 7.32-7.39 (2H, m).

¹³C-NMR (CDCl₃): 29.6; 31.0; 34.2; 37.7; 38.0; 38.3; 41.2; 52.8; 53.4; 60.5; 65.4; 71.0; 126.4; 127.6; 127.61.

LC-MS (method 1): m/z: [M+H]⁺=345.4, R_(t)=0.4 min.

Example No. 275 3-(2-Cyclopropyiethyl)-8-methylamino-8-phenyl-3-azaspiro[4.5]decan-2-one (Example no. 275, non-polar diastereoisomer)

N-Iodosuccinimide (348 mg, 1.55 mmol) was added to a solution of 3-(2-cyclopropylethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one (Ex. no. 184, non-polar series, 350 mg, 1.03 mmol) in anhydrous acetonitrile (10 ml) and the mixture was stirred for 5 h at room temperature. 4 M sodium hydroxide solution (3 ml) was then added to the reaction solution and the mixture was stirred for 20 min at room temperature. The phases were separated and the aqueous phase was extracted with methylene chloride (2×10 ml). The combined organic phases were concentrated i. vac. The residue (550 mg) was taken up in methanol (5 ml), 2 M hydrochloric acid (2 ml) was added to the solution and the mixture was stirred for 1 h at room temperature. The solution was then diluted with water (10 ml) and washed with diethyl ether (3×10 ml). The aqueous solution was rendered alkaline (pH ˜10) with 2 M sodium hydroxide solution and extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (240 mg) was purified by means of flash chromatography on PharmPrep 60 CC (12 g, 18×1.5 cm) with methylene chloride/methanol (50:1)+0.5% ammonia (25% in water) and subsequent renewed flash chromatography on PharmPrep 60 CC (4 g, 14×1.0 cm) with methanol.

Example No. 275 Non-Polar Diastereoisomer

Yield: 155 mg (46%), colourless resin

¹H-NMR (CDCl₃): 0.04-0.08 (2H, m); 0.42-0.49 (2H, m); 0.59-0.70 (1H, m); 1.42 (2H, dd, J=14.4 and 7.01 Hz); 1.45-1.53 (2H, m); 1.73-1.99 (7H, m); 2.00 (3H, s); 2.24 (2H, s); 3.22 (2H, s); 3.32-3.37 (2H, m); 7.18-7.28 (1H, m); 7.32-7.39 (4H, m).

¹³C-NMR (CDCl₃): 4.3; 8.6; 28.6; 31.9; 32.4; 32.5; 35.8; 38.0; 42.6; 56.9; 59.7; 125.9; 126.5; 128.4; 173.5.

LC-MS: m/z: [M+H]⁺=327.3, R_(t)=2.6 min.

Example No. 337 Step 1: 8-Dimethylamino-8-[1.2.3]triazol-1-yl-2-azaspiro[4.5]decan-3-one

A 2 M dimethylamine solution in tetrahydrofuran (1.8 ml, 3.6 mmol), 1,2,3-triazole (228 mg, 191 μl, 3.3 mmol) and a molecular sieve 4 Å (1.00 g) were added to a solution of 2-azaspiro[4.5]decane-3,8-dione (500 mg, 3 mmol) in anhydrous tetrahydrofuran (30 ml) and the mixture was stirred for 18 h at room temperature. The reaction mixture was filtered and the filtrate was concentrated i. vac.

Yield: 704 mg (89%), white solid

Step 2: 8-(5-Chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-3-one

A suspension of 8-dimethylamino-8-[1.2.3]triazol-1-yl-2-azaspiro[4.5]decan-3-one (2.10 g, maximum 8 mmol) in anhydrous tetrahydrofuran (60 ml) was added dropwise to a 0.5 M suspension of 5-chloro-2-thienylmagnesium bromide (45 ml, 22.5 mmol) in tetrahydrofuran at room temperature and the mixture was then stirred for 6 h at 50° C. and for 18 h at room temperature. After addition of saturated ammonium chloride solution (100 ml) the phases were separated and the aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and filtered and the filtrate was concentrated i. vac.

Yield: 1.95 g (>100%), brown solid

The ¹H-NMR spectrum (CDCl₃) shows all the required signals of the diastereoisomer mixture.

LC-MS: m/z: [M+H]⁺=313.2, R_(t)=2.3 min.

Step 3:8-(5-acid tert-butyl ester (polar and non-polar diastereoisomer)

Di-tert-butyl dicarbonate (1.92 g, 8.8 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol) were added to a solution of 8-(5-chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-3-one (1.70 g, maximum 8 mmol) in anhydrous tetrahydrofuran (30 ml) and anhydrous acetonitrile (50 ml) and the mixture was stirred for 18 h at room temperature. After 4 h and 1 d in each case di-tert-butyl dicarbonate (1.92 g, 8.8 mmol) and dimethylaminopyridine (100 mg, 0.8 mmol) were added and the mixture was then stirred for 4 d at room temperature. The reaction mixture was concentrated i. vac., the residue was taken up in methylene chloride (100 ml) and the solution was washed with water (3×50 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (1.70 g) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol (30:1).

Nonpolar Diastereoisomer

Yield: 224 mg (7%), brown oil

¹H-NMR (CDCl₃): 1.42-1.50 (3H, m); 1.52 (9H, s); 1.75-1.83 (2H, m); 1.90-2.03 (3H, m); 2.12 (6H, s); 2.32 (2H, s); 3.56 (2H, s); 6.60 (1H, d, J=3.8 Hz); 6.85 (1H, d, J=3.8 Hz).

Polar Diastereoisomer

Yield: 260 mg (8%), brown oil

¹H-NMR (CDCl₃): 1.44-1.50 (3H, m); 1.50 (9H, s); 1.70-1.78 (2H, m); 1.88-2.03 (3H, m); 2.11 (6H, s); 2.43 (2H, s); 3.44 (2H, s); 6.61 (1H, d, J=3.8 Hz); 6.85 (1H, d, J=3.8 Hz).

Step 4: 8-(5-Chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-3-one

Trifluoroacetic acid (2 ml) was added to a solution of 8-(5-chlorothiophen-2-yl)-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (non-polar diastereoisomer) (224 mg, 0.54 mmol) in anhydrous methylene chloride (20 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated i. vac., methylene chloride (20 ml) was added to the residue and the solution was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Non-Polar Diastereoisomer

Yield: 126 mg (74%), brown solid

Melting point: 170-175° C.

¹H-NMR (CDCl₃): 1.46-1.55 (2H, m); 1.76-1.85 (2H, m); 1.90-2.01 (4H, m); 2.11 (6H, s); 2.14 (2H, s); 3.22 (2H, s); 5.55 (1H, br s); 6.61 (1H, d, J=3.8 Hz); 6.85 (1H, d, J=3.8 Hz).

Trifluoroacetic acid (2 ml) was added to a solution of 8-(5-chlorothiophen-2-yl)-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (polar diastereoisomer) (155 mg, 0.37 mmol) in anhydrous methylene chloride (20 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated i. vac., methylene chloride (20 ml) was added to the residue and the mixture was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Polar Diastereoisomer

Yield: 66 mg (56%), brown solid

¹H-NMR (CDCl₃): 1.46-1.54 (2H, m); 1.75-1.83 (2H, m); 1.89-2.03 (4H, m); 2.12 (6H, s); 2.25 (2H, 5); 3.10 (2H, 5); 5.48 (1H, br s); 6.61 (1H, d, J=3.8 Hz); 6.85 (1H, d, J=3.8 Hz).

Step 5: 8-(5-Chlorothiophen-2-yl)-8-(dimethylamino)-3-(3-methoxy-3-methylbutyl)-3-azaspiro[4.5]decan-2-one (Example no. 460, non-polar diastereoisomer)

A suspension of powdered sodium hydroxide dried in vacuo (96 mg, 2.4 mmol) in anhydrous dimethylsulfoxide (10 ml) was stirred for 40 min at room temperature and 8-(5-chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-3-one (non-polar series, 126 mg, 0.41 mmol) and 3-methoxy-3-methylbut-1-yl tosylate (136 mg, 0.5 mmol) were then added. Thereafter the reaction mixture was stirred for 1 d at room temperature. After addition of water (50 ml) the reaction mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried with sodium sulfate and filtered and the filtrate was concentrated i. vac. Toluene was repeatedly added to the residue and each time the mixture was concentrated i. vac. The crude product (152 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 0.5% ammonia (25% in water).

Example No. 337 Non-Polar Diastereoisomer

Yield: 98 mg (58%), yellow solid.

Melting point: 86-90° C.

¹H-NMR (CDCl₃): 1.18 (6H, s); 1.41-1.49 (2H, m); 1.62-1.69 (2H, m); 1.70-1.79 (2H, m); 1.91-2.00 (4H, m); 2.10 (6H, s); 2.18 (2H, s); 3.19 (3H, s); 3.20 (2H, s); 3.28-3.34 (2H, m); 6.60 (1H, d, J=3.8 Hz); 6.84 (1H, d, J=3.8 Hz).

¹³C-NMR (CDCl₃): 24.9; 32.4; 32.6; 35.5; 36.8; 38.0; 38.2; 44.3; 49.2; 58.0; 59.6; 73.5; 124.2; 124.5; 127.8; 173.2.

LC-MS: m/z: [M+H]⁺=414.3, R_(t)=2.8 min.

Example No. 364 Step 1: (8-Butyl-2-azaspiro[4.5]dec-8-yl)-dimethylamine

A solution of Example no. 19 (5.00 g, 19.8 mmol) in anhydrous tetrahydrofuran (50 ml) was added to a suspension of lithium aluminium hydride (3.01 g, 79.2 mmol) in anhydrous tetrahydrofuran (50 ml) in a thoroughly heated apparatus, while cooling with ice, and the mixture was stirred for 18 h at 50° C. and then for 72 h at room temperature. Water (3 ml), 15% strength sodium hydroxide solution (3 ml) and again water (9 ml) were added dropwise to the reaction mixture, while cooling with ice, and the mixture was stirred for 2 h at room temperature. The suspension was then filtered through sea sand, the residue was washed with tetrahydrofuran and the filtrate was dried with sodium sulfate and concentrated i. vac. The residue was taken up several times in methylene chloride (3×25 ml) and the solution was in each case concentrated again i. vac. again.

Yield: 4.71 g (100%), yellow oil

¹H-NMR (CDCl₃): 0.87 (3H, t, J=7.1 Hz); 1.14-1.33 (10H, m); 1.44-1.57 (8H, m); 2.13 (6H, s); 2.80 (2H, t, J=7.1 Hz); 3.65 (1H, br s).

Step 2: 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-cyclopropylethanone (Example no. 364, polar diastereoisomer)

N,N′-Carbonyldiimidazole (122 mg, 0.8 mmol) was added to a solution of cyclopropylacetic acid (137 mg, 1.4 mmol) in absolute tetrahydrofuran (10 ml) and the mixture was stirred for 2 h under reflux. Thereafter a solution of (8-butyl-2-azaspiro[4.5]dec-8-yl)-dimethylamine (238 mg, 1.0 mmol) in absolute tetrahydrofuran (10 ml) was added and the mixture was stirred for a further 2 h under reflux. The reaction solution was then concentrated I. vac. and the residue was taken up in ethyl acetate (40 ml). The solution obtained was washed with 1 M potassium carbonate solution (2×20 ml), water (3×20 ml) and saturated sodium chloride solution (20 ml), dried with sodium sulfate and concentrated i. vac. The crude product (210 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with ethyl acetate/methanol (9:1).

Example No. 364 Polar Diastereoisomer

Yield: 93 mg (33%), yellow oil

¹H-NMR (CDCl₃): 0.13-0.17 (2H, m); 0.52-0.57 (2H, m); 0.91 (3H, t, J=7.1 Hz); 1.04-1.13 (1H, m); 1.16-1.46 (10H, m); 1.50-1.67 (4H, m, overlapped by the water signal), 1.72 (0.8 H, t, J=7.2 Hz); 1.78 (1.2H, t, J=7.1 Hz); 2.19 (2H, m); 2.21 (3H, s); 2.22 (3H, s); 3.18 (1H, s); 3.30 (1H, s); 3.43 (0.8H, t, J=7.1 Hz); 3.52 (1.2H, t, J=7.2 Hz).

¹³C-NMR (CDCl₃): 4.42; 4.44; 6.9; 7.0; 14.17; 14.20; 23.76; 23.81; 26.2, 26.6, 28.1; 28.9; 30.2; 30.5, 30.6; 30.8; 33.8; 36.3; 37.3; 37.4; 39.5; 39.9; 40.3; 42.2; 44.2; 45.3; 56.4; 56.5; 58.8; 171.40; 171.44.

LC-MS: m/z: [M+H]⁺=321.4 (100%), R_(t)=2.8 min.

Example No. 408 Step 1: Dimethyl-(8-phenyl-2-azaspiro[4.5]dec-8-yl)amine

A solution of Example 431 (8-dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one) (non-polar, diastereoisomer, 327 mg, 1.2 mmol) in anhydrous tetrahydrofuran (25 nil) was added dropwise to a suspension of lithium aluminium hydride (114 mg, 3 mmol) in anhydrous tetrahydrofuran (10 ml) under argon and the mixture was then stirred for 18 h at room temperature. Since the reaction was not complete, the mixture was heated to 50° C. and stirred for a further 3 h. After addition of water (200 μl), 1 M sodium hydroxide solution (500 μl) and water (500 μl) the mixture was stirred for 1 h and the suspension was filtered through sea sand. The filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 310 mg (100%), colourless oil

¹H-NMR (CDCl₃): 1.23-1.32 (2H, m); 1.54-1.62 (2H, m); 1.85 (2H, t, J=7.1 Hz); 1.85-1.96 (2H, m), 2.04 (6H, s); 2.05-2.11 (1H, m); 2.23-2.35 (2H, m); 2.53 (2H, s); 2.95 (2H, t, J=7.1 Hz); 7.26-7.32 (3H, m); 7.34-7.40 (2H, m).

Step 2: 2-Cyclopropyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethanone (Example no. 408, non-polar diastereoisomer)

N,N′-Carbonyldiimidazole (130 mg, 0.8 mmol) was added to a solution of cyclopropylacetic acid (100 mg, 96 μl, 1 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred for 2 h under reflux. After addition of dimethyl-(8-phenyl-2-azaspiro[4.5]dec-8-yl)amine (155 mg, 0.6 mmol) in anhydrous tetrahydrofuran (5 ml) the solution was stirred for a further 2 h under reflux. The reaction mixture was then concentrated i. vac., the residue was taken up in ethyl acetate (30 ml) and the solution was washed with 2 M potassium carbonate solution (3×30 ml), water (3×30 ml) and saturated sodium chloride solution (30 ml). The organic phase was separated off, dried with sodium sulfate and filtered and the filtrate was concentrated i. vac. The crude product (210 mg) was purified by flash chromatography (10 g, 20×1.5 cm) with methylene chloride/methanol (95:5) and 0.5° A ammonia (25% in water).

Example No. 408 Non-Polar Diastereoisomer

Yield: 65 mg (32%), colourless oil

¹H-NMR (CDCl₃): 0.06-0.16 (2H, m); 0.47-0.57 (2H, m); 0.97-1.12 (1H, m); 1.24-1.40 (3H, m); 1.60-1.70 (3H, m); 1.80 (1H, t, J=7.2 Hz); 1.88 (1H, t, J=7.1 Hz); 2.04 (6H, s); 2.07-2.22 (4H, m); 3.06 and 3.18 (2H, 2 s); 3.46 (1H, t, J=7.1 Hz); 3.54 (1H, t, J=7.2 Hz); 7.26-7.32 (3H, m); 7.33-7.41 (2H, m).

¹³C-NMR (CDCl₃): 4.36; 4.42; 30.4; 30.5; 31.1; 34.2; 38.1; 39.4; 39.8; 40.3; 42.3; 44.2; 45.3; 58.0; 60.6; 126.7; 127.4; 127.5; 127.7; 171.4.

LC-MS: m/z: [M+H]⁺=341.3, R_(t)=2.8 min.

Example No. 417 Step 1: [4-Dimethylamino-4-(5-fluorothiophen-2-yl)-cyclohexylidene]-acetic acid ethyl ester

Potassium tert-butanolate (1.21 g, 10.8 mmol) was added to a solution of phosphonoacetic acid triethyl ester (2.73 g, 2.42 ml, 12.2 mmol) in anhydrous N,N-dimethylformamide (15 ml) and the mixture was stirred for 1 h at 50° C. The solution was cooled to room temperature and a solution of 4-(dimethylamino)-4-(5-fluorothiophen-2-yl)cyclohexanone (1.85 g, 7.66 mmol) in anhydrous N,N-dimethylformamide (20 ml) was then added. The reaction mixture was stirred for 20 h at room temperature and then poured into ice-water (30 g). The suspension was extracted with diethyl ether (4×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. Toluene was repeatedly added to the residue and cyclohexane was then repeatedly added and in each case the mixture was concentrated again i. vac. The residue (2.42 g) was taken up in ethyl acetate (30 ml) and the solution was extracted with 10% strength aqueous formic acid (5×30 ml). The combined acid, aqueous phases were rendered alkaline with 4 N sodium hydroxide solution and extracted with methylene chloride (5×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac.

Yield: 2.0 g (84%), yellowish oil.

¹H-NMR (CDCl₃): 1.27 (3H, t, J=7.1 Hz); 1.90-2.08 (2H, m); 2.09-2.28 (4H, m); 2.17 (6H, s); 2.82-2.96 (1H, m); 3.00-3.15 (1H, m); 4.14 (2H, q, J=7.1 Hz); 5.62 (1H, s); 6.38 (1H, dd, J=3.9 and 1.6 Hz); 6.47 (1H, t, J=3.5 Hz).

Step 2: [4-Dimethylamino-4-(5-fluorothiophen-2-yl)-1-nitromethylcyclohexyl]-acetic acid ethyl ester

Tetra-n-butylammonium fluoride trihydrate (555 mg, 1.8 mmol) and nitromethane (5.40 g, 4.79 ml, 88 mmol) were added to a solution of [4-dimethylamino-4-(5-fluorothiophen-2-yl)-cyclohexylidene]-acetic acid ethyl ester (500 mg, 1.6 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 3 h at 70° C. and then for 18 h at 45° C. The reaction solution was then concentrated i. vac. and the residue (1.31 g) was purified by flash chromatography on spherical silica gel (PuriFlash PF-50SIHP, 50 μm, 100 g, 20×4.0 cm) with cyclohexane/ethyl acetate (2:1→1:1). The target compound is obtained as a diastereoisomer mixture (approx. 1:1).

Yield: 415 mg (70%), pale yellow viscous oil

¹H-NMR (CDCl₃): 1.24 and 1.26 (3H, 2 t, J=7.1 Hz); 1.46-1.53 (2H, m), 1.77-1.86 (2H, m); 1.93-2.01 (4H, m); 2.10 (6H, s); 2.48 (1H, s); 2.60 (1H, s); 4.12 and 4.16 (2H, 2 q, J=7.2 Hz); 4.64 (1H, s); 4.76 (1H, s); 6.38-6.43 (2H, m).

LC-MS: m/z: [M+H]⁼373.32 (55%) and [MH-NHMe₂]⁺=328.2 (100%), R_(t)=2.7 and 2.9 min.

Step 3: 8-Dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decan-3-one

A solution of [4-dimethylamino-4-(5-fluorothiophen-2-yl)-1-nitromethylcyclohexyl]-acetic acid ethyl ester (415 mg, 1.1 mmol) in ethanol (10 ml) was added to a mixture of iron powder (307 mg, 5.5 mmol), ammonium chloride (1.42 g, 28 mmol) and water (1.1 ml) and the mixture was then stirred for 4 h at 80° C. The reaction mixture was filtered and the residue was washed with ethanol. The ethanolic solution was rendered alkaline with 5% strength sodium bicarbonate solution and the ethanol was removed i. vac. The aqueous suspension was extracted with methylene chloride (3×20 ml), the combined organic phases were washed with saturated sodium chloride solution (20 ml) and filtered through phase separation paper and the filtrate was concentrated i. vac. The crude product (306 mg) was cyclised completely.

Step 4: 8-Dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decan-3-one

Potassium tert-butylate (419 mg, 3.7 mmol) was added to a solution of step 3 (900 mg, 3.0 mmol) in anhydrous tetrahydrofuran (40 ml) and the mixture was stirred for 18 h overnight at room temperature. Saturated ammonium chloride solution (5 ml) was then added to the reaction solution, the mixture was concentrated i. vac. and water (50 ml) was added to the residue. The aqueous solution was extracted with methylene chloride (4×30 ml), the combined organic phases were washed with saturated sodium chloride solution (30 ml) and filtered through phase separation paper and the filtrate was concentrated i. vac.

Yield: 662 mg (66%), pale yellow, viscous foam

¹H-NMR (CDCl₃): 1.47-1.54 (2H, m); 175-1.83 (2H, m); 1.90-2.00 (4H, m); 2.116 (3H, s); 2.119 (3H, s); 2.14 (1H, s); 2.25 (1H, s); 3.10 (1H, s); 3.22 (1H, s); 5.55 (1H, br s); 6.38-6.40 (1H, m); 8.42-6.44 (1H, m).

LC-MS: m/z: [M+H]⁺=297.3 (60%) and [MH-NHMe₂]⁺=252.2 (100%), R_(t)=1.8 min.

This is a diastereoisomer mixture in the ratio of approx. 1:1.

Step 5: 8-Dimethylamino-8-(5-fluorothiophen-2-yl)-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (polar and non-polar diastereoisomer)

Di-tert-butyl dicarbonate (528 mg, 2.4 mmol) and 4-dimethylaminopyridine (25 mg, 0.2 mmol) were added to a solution of 8-dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decan-3-one (660 mg, crude product, maximum 2.2 mmol) in a mixture of anhydrous tetrahydrofuran (25 ml) and anhydrous acetonitrile (25 ml) and the mixture was stirred for 18 h at 50° C. The reaction solution was then concentrated i. vac. and the diastereoisomer mixture (890 mg) was separated by flash chromatography on spherical silica gel (PuriFlash PF-50SIHP, 50 μm, 38 g, 20×2.5 cm) with ethyl acetate which contained 1% methanol.

Non-Polar Diastereoisomer

Yield: 447 mg (51%), pale yellow solid

Melting point: 130-132° C.

¹H-NMR (CDCl₃): 1.43-1.51 (2H, m); 1.53 (9H, s); 175-1.81 (2H, m); 1.89-2.02 (4H, m); 2.12 (6H, s); 2.33 (2H, s); 3.58 (3H, s); 6.39 (1H, dd, J=1.6 and 4.1 Hz); 8.42-0.43 (1H, m).

Polar Diastereoisomer

Yield: 337 mg (41%), pale yellow solid

Melting point: 152-155° C.

¹H-NMR (CDCl₃): 1.46-1.51 (2H, m, overlapped); 1.51 (9H, s); 1.71-1.77 (2M, m); 1.88 (4H, m); 2.11 (6H, s); 2.43 (2H, s); 3.45 (2H, s); 6.39 (1 M, dd, J=1.5 and 4.1 Hz); 6.42-6.44 (1H, m).

Step 6: 8-Dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer)

Trifluoroacetic acid (2.5 ml, 25% v/v) was added to a solution of 8-dimethylamino-8-(5-fluorothiophen-2-yl)-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (non-polar series, 430 mg, 1.1 mmol) in absolute methylene chloride (10 m) and the mixture was stirred for 1 h at room temperature. The reaction solution was then concentrated I. vac. and the residue was taken up in methylene chloride (50 ml). The solution was washed with 1 M potassium carbonate solution (3×30 ml) and saturated sodium chloride solution (30 ml) and filtered through phase separation paper and the filtrate was concentrated i. vac.

Non-Polar Diastereoisomer:

Yield: 248 mg (77%), pale pink-coloured solid

Melting point: 198-204° C.

¹H-NMR (CDCl₃): 1.48-1.54 (2H, m); 1.76-1.83 (2H, m); 1.91-1.97 (4H, m); 2.11 (6H, s); 2.14 (2H, s); 3.22 (2H, s); 5.70 (1H, br s); 6.39 (1H, dd, J=1.7 and 4.0 Hz); 6.42-6.44 (1H, m).

¹³C-NMR (CDCl₃): 32.0; 32.1; 32.4; 38.0; 38.9; 43.0; 52.5; 59.5; 106.3; 106.4; 121.1; 162.5; 165.4; 177.2.

LC-MS: m/z: [M+H]⁺=297.2 (72%) and [MH-NHMe₂]⁺=252.2 (100%), R_(t)=1.7 min.

Step 7: 1-[8-Dimethylamino-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-3-methoxy-3-methylbutan-1-one (Example no. 549, non-polar diastereoisomer)

A suspension of powdered sodium hydroxide dried i. vac. (70 mg, 1.8 mmol) in absolute dimethylsulfoxide (5 ml) was stirred for 20 min at room temperature. A solution of 8-dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer, 130 mg, 0.44 mmol) in absolute dimethylsulfoxide (5 ml) and a solution of 3-methoxy-3-methylbut-1-yl tosylate (144 mg, 0.53 mmol) in dimethylsulfoxide (5 ml) were then added to this and the mixture was stirred for 4 h at 80° C. Thereafter water (50 ml) was added to the reaction solution and the mixture was extracted with ethyl acetate (4×20 ml). The combined organic phases were washed with saturated sodium chloride solution (20 ml) and filtered through phase separation paper and the filtrate was concentrated i. vac. Toluene and methylene chloride (3×10 ml of each) were added several times in succession to the residue and the mixture was in each case concentrated again i. vac. at 60° C. in order to remove dimethylsulfoxide without trace. The crude product (154 mg) was purified by means of flash chromatography on spherical silica gel (PuriFlash PF-50SIHP, 50 μm, 5 g, 15×0.9 cm) with ethyl acetate/methanol (9:1).

Example No. 417 Non-Polar Diastereoisomer

Yield: 116 mg (67%), white solid

Melting point: 93° C.

¹H-NMR (CDCl₃): 1.18 (6H, m); 1.43-1.49 (2H, m); 1.64-1.68 (2H, m); 1.71-1.77 (2H, m); 1.91-1.97 (4H, m); 2.11 (6H, s); 2.19 (2H, s); 3.19 (3H, s); 3.21 (2H, s); 3.30-3.34 (2H, m); 6.39 (1H, dd, J=1.7 and 3.9 Hz); 6.41-6.43 (1H, m).

¹³C-NMR (CDCl₃): 24.9; 32.2; 32.6; 35.5; 36.8; 38.0; 38.3; 44.4; 49.2; 59.5; 73.6; 106.3; 106.4; 121.1; 162.5; 165.4; 173.3.

LC-MS: m/z: [M+H]⁺=397.3 (100%) and [MH-NHMe₂]⁺=352.3 (35%), R_(t)=2.6 min.

Example No. 424 Step 1: 8-Cyclopent-1-enyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one

A solution of cyclopentenylmethylmagnesium bromide (maximum 17 mmol) was added dropwise to a solution of 8-(dimethylamino)-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (958 mg, 4.32 mmol) in anhydrous tetrahydrofuran (20 ml) and the mixture was stirred for 1 h at room temperature. The mixture was heated to 60° C. and stirred for 1 h at this temperature. Saturated ammonium chloride solution (25 ml) and water (20 ml) were added to the suspension, while cooling with ice. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The residue (900 mg) was purified by flash chromatography (85 g, 4.0×20 cm) with methylene chloride/methanol (9:1) and 1% ammonia (25% in water).

Yield: 527 mg (46%), white solid

¹H-NMR (CDCl₃): 1.18-1.26 (2H, m); 1.31-1.41 (2H, m); 1.75-1.85 (2H, m); 1.97 (2H, t, J=6.9 Hz); 2.01-2.10 (2H, m); 2.11-2.20 (2H, m); 2.18 (6H, s); 2.22-2.36 (4H, m); 3.25 (2H, m); 5.44 (1H, m); 6.38 (1H, br s).

¹³C-NMR (CDCl₃): 23.6; 28.2; 29.1; 31.9; 32.9; 34.0; 38.3; 38.6; 38.8; 43.2; 56.9; 125.8; 146.0; 183.2.

LC-MS: [M+H]⁺: m/z=263.4, R₁=2.3 min.

Step 2: 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one

5% rhodium on aluminium oxide (960 mg, 0./47 mmol) was added to a solution of 8-cyclopent-1-enyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one (2.5 g, 9.5 mmol) in anhydrous methanol (20 ml) and the mixture was stirred for 3 h under a hydrogen pressure of 2 bar. Methanol (20 ml) was added to the mixture again and the mixture was stirred for a further 2 h under a hydrogen pressure of 2 bar. Since the educt had not yet reacted, the reaction mixture was diluted with methanol (110 ml), 5% rhodium on aluminium oxide (1.92 g, 0.95 mmol) was again added and hydrogen was carried out for 20 h under a hydrogen pressure of 4 bar. The suspension was filtered through Celite, the residue was washed with methanol and the filtrate was concentrated i. vac. The residue was partitioned between ethyl acetate and 10% strength citric acid solution (40 ml of each). The organic phase was washed with 10% strength citric acid solution (3×80 ml). The combined acid, aqueous phases were rendered alkaline with 4 M sodium hydroxide solution and extracted with methylene chloride (4×50 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (202 mg) was purified by flash chromatography (85 g, 20×4.0 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water).

Yield: 757 mg (30%), white solid

¹H-NMR (CDCl₃): 1.14 (2H, dd, J=11.8 and 1.2 Hz); 1.20-1.34 (4H, m); 1.40-1.63 (6H, m); 1.73 (2H, dd, J=14.9 and 2.8 Hz); 1.98-2.14 (5H, m); 2.28 (6H, s); 3.29-3.30 (2H, m); 6.20 (1H, s).

¹³C-NMR (CDCl₃): 25.0; 26.5; 27.3; 28.3; 31.9; 37.9; 38.9; 44.2; 44.4; 57.4; 183.4.

LC-MS: [M+H]⁺: m/z=265.4.4; Rt=2.2 min.

Step 3: 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decane

A solution of 8-cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decan-1-one (758 mg, 2.8 mmol) in anhydrous tetrahydrofuran (30 ml) was added dropwise to a suspension of lithium aluminium hydride (542 mg, 14.3 mmol) in anhydrous tetrahydrofuran (10 ml), while cooling with ice. The suspension was stirred for 4 h at 50° C. Water (560 μl), 1 M sodium hydroxide solution (1.1 ml) and again water (1.1 ml) were added to the mixture, while cooling with ice. The suspension was stirred for 1 h at room temperature and then filtered through sodium sulfate. The residue was washed with tetrahydrofuran and the filtrate was concentrated vac.

Yield: 689 mg (96%), colourless oil

¹H-NMR (CDCl₃): 1.11-1.20 (2H, m); 1.22-1.38 (4H, m); 1.40-1.70 (12H, m); 1.98 (1H, br s); 2.05 (1H, m); 2.26 (6H, s); 2.61 (2H, s); 2.93 (2H, t, J=7.0 Hz).

Example No. 425 Step 1: 8-(5-Chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-4-one

A suspension of 8-(dimethylamino)-1-oxo-2-azaspiro[4.5]decane-8-carbonitrile (1.76 g, 7.9 mmol) in absolute tetrahydrofuran (75 ml) was slowly added dropwise to a 0.5 M suspension of 5-chloro-2-thienylmagnesium bromide (5.29 g, 48 ml, 23.9 mmol) in tetrahydrofuran under argon, a clear solution being formed. The solution was then stirred overnight at 50° C. After addition of saturated ammonium chloride solution (100 ml) the tetrahydrofuran was removed i. vac. The aqueous solution obtained was extracted with methylene chloride (3×50 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac.

The crude product (2.45 g) was purified by means of flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol (97:3).

Yield: 1.47 g (59%), yellow solid.

Melting point: 198-201° C.

¹H-NMR (CDCl₃): 1.28-1.34 (2H, m); 1.61-1.68 (2H, m); 2.01 (2H, t, J=6.9 Hz); 2.12 (6H, s); 2.17 (2H, dt, J=13.1 and 3.1 Hz), 2.32-2.40 (2H, m); 3.28-3.32 (2H, m); 5.90 (1H, br s); 6.60 (1H, d, J=3.8 Hz); 6.83 (1H, d, J=3.8 Hz).

¹³C-NMR (CDCl₃): 27.9; 31.5; 32.7; 37.9; 38.7; 43.1; 58.9; 123.1; 125.2, 127.4; 144.4; 182.4. LC-MS: m/z: [MH-HNMe₂]⁺=268.2, R_(t)=2.6 min.

Step 2: [8-(5-Chloro-2-thiophen-2-yl)-2-azaspiro[4.5]dec-8-yl]-dimethylamine (Example no. 425)

A 2 M solution of boron-dimethyl sulfide complex in tetrahydrofuran (6.42 ml, 12.8 mmol) was added to a solution of 8-(5-chlorothiophen-2-yl)-8-dimethylamino-2-azaspiro[4.5]decan-4-one (1.34 g, 4.3 mmol) in absolute tetrahydrofuran (150 ml) and the mixture was stirred for 4 h under reflux and overnight at 50° C. Since the reaction was not yet complete, this same amount of 2 M borane-dimethyl sulfide complex was again added and the mixture was stirred for a further 6 h under reflux and over the weekend at room temperature. Water (100 ml) was added to the reaction solution and the mixture was concentrated i. vac. Toluene, methanol and methylene chloride (3×30 ml of each) were added in succession to the residue and the mixture was again concentrated i. vac. The crude product was reacted further without purification.

Yield: 1.95 g (151%), viscous yellow oil

The ¹H-NMR spectrum shows all the expected signals.

LC-MS: m/z: [MH-HNMe₂]⁺=254.3, R_(t)=2.7 min.

The product content is a maximum of 66%.

Example No. 426 Step 1: 8-Dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester

A 2.5 M solution of n-butyllithium in hexane (2.2 ml, 5.5 mmol) was added dropwise to a solution of 8-dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decane-3-carboxylic acid tert-butyl ester (Example no. 79) (1.55 g, 4.3 mmol) in absolute tetrahydrofuran (100 ml) in a thoroughly heated apparatus at −78° C. under argon and the mixture was stirred for 30 min at this temperature. The solution became yellow in colour. A solution of N-benzenesulfonyl-N-fluorobenzenesulfonamide (1.74 g, 5.5 mmol) in absolute tetrahydrofuran (50 ml) was added dropwise to this and the mixture was then warmed slowly to room temperature and further stirred for 18 h at this temperature. The solution became red in colour. After addition of saturated ammonium chloride solution (50 ml) the tetrahydrofuran was removed i. vac. The aqueous solution obtained was extracted with methylene chloride (3×30 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac. The crude product (2.50 g) was purified by flash chromatography on spherical silica gel (PharmPrep 60 CC, 40-63 μm, 100 g, 20×4.0 cm) with ethyl acetate/isopropanol (99:1).

Yield: cannot be determined since various mixed fractions of differing purity were obtained, orange-coloured viscous oil

¹H-NMR (CDCl₃): 1.34-1.42 (2H, m); 1.46 (9H, s); 1.57-1.66 (4H, m); 1.78-1.97 (4H, m); 2.11 (2H, s); 2.13 (4H, s); 3.18 (0.7 H, s); 3.22 (1.3 H, s); 3.32 (0.7 H, t, J=7.1 Hz); 3.37 (1.3 H, t, J=7.1 Hz); 6.35-6.40 (1H, m); 6.42 (1H, t, J=3.5 Hz).

¹³C-NMR (DMSO-d₅): 28.6; 31.3; 32.1; 32.9; 36.6; 37.0; 38.1; 40.7; 41.5, 44.0; 44.4; 55.6, 60.2; 79.1; 106.3; 121.3; 154.8; 162.5; 165.4.

Some C signals are doubled due to the amide structure (rotamers). For this reason, also no C-F coupling constants were determined.

LC-MS: m/z: [MH-NHMe₂]⁺=383.4, R_(t)=3.3 min.

Step 2: [8-(5-Fluorothiophen-2-yl)-2-azaspiro[4.6]dec-8-yl]-dimethylamine (Example 426)

Trifluoroacetic acid (15 ml) was added to a solution of 8-dimethylamino-8-(5-fluorothiophen-2-yl)-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.35 g, max. 3.5 mmol, slightly contaminated) in absolute methylene chloride (60 ml) and the mixture was stirred for 1 h at room temperature. The reaction solution was concentrated i. vac. and methylene chloride (50 ml) was added to the residue. The solution obtained was washed with saturated potassium bicarbonate solution (3×30 ml) and saturated sodium chloride solution (50 ml), dried with sodium sulfate and concentrated i. vac. The crude product was reacted further without purification.

Yield: 738 mg (crude product), orange-coloured viscous oil

¹H-NMR (CDCl₃): 1.43 (2H, ddd, J=13.1, 8.1 and 4.9 Hz); 1.61 (2H, t, J=7.3 Hz); 1.68-1.74 (2H, m); 1.86-1.99 (4H, m); 2.10 (6H, s); 2.88 (2H, s); 3.09 (2H, t, J=7.3 Hz); 5.02 (1H, br. s); 6.38 (1H, dd, J=4.0 and 1.7 Hz); 6.42 (1H, dd, J=4.0 and 3.1 Hz).

Example No. 427 Step 1: 2-[4-(Azetidin-1-yl)-4-(2-thienyl)cyclohexylidene]-acetic acid ethyl ester

Potassium tert-butylate (2.82 g, 25.1 mmol) was added to a solution of phosphonoacetic acid triethyl ester (5.60 g, 4.8 ml, 25.1 mmol) in anhydrous N,N-dimethylformamide (30 ml) under argon and the mixture was stirred for 10 min at room temperature. A solution of 4-(azetidin-1-yl)-4-(thiophen-2-yl)cyclohexanone (3.96 g, 16.8 mmol) in anhydrous N,N-dimethylformamide (60 ml) was then added to the mixture and the mixture was stirred for 1 h at room temperature and then poured into ice-water (80 g). The aqueous suspension was extracted with diethyl ether (4×40 ml). The combined organic extracts were dried with sodium sulfate and concentrated i. vac.

Yield: 4.79 g (93%), brownish oil

¹H-NMR (CDCl₃): 1.26 (t, 3H, J=7.1 Hz); 1.76-1.85 (m, 2H); 1.87-2.02 (m, 4H); 2.12-2.20 (m, 1H); 2.44-2.57 (m, 1H); 2.89-3.05 (m, 2H); 3.11 (t, 4H, J=6.9 Hz); 4.13 (q, 2H, J=7.1 Hz); 5.61 (br s, 1H); 6.89 (d, 1H, J=3.5 Hz); 7.08 (dd. 1H, J=5.1, 1.5 Hz); 7.25-7.28 (m, 1H, overlapped by the CDCl₃ signal).

Step 2: 2-[4-(Azetidin-1-yl)-1-(nitromethyl)-4-(2-thienyl)cyclohexyl]-acetic acid ethyl ester

Nitromethane (1.24 g, 1.09 ml, 20.3 mmol) was added to a mixture of 2-[4-(azetidin-1-yl)-4-(2-thienyl)cyclohexylidene]-acetic acid ethyl ester (4.79 g, 15.7 mmol) and tetra-n-butylammonium fluoride trihydrate (5.43 g, 17.2 mmol) in tetrahydrofuran (150 ml) and the mixture was stirred for 6 h at 70° C. and for 18 h at 45° C. The reaction mixture was then concentrated in vacuo and the crude product (12.0 g) was purified by flash chromatography (200 g, 20×5.7 cm) with ethyl acetate/cyclohexane (9:1).

Yield: 4.18 g (74%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.10-1.24 (m, 3H); 1.37-1.47 (m, 2H); 1.63-1.86 (m, 8H); 2.42 and 2.46 (2 s, 2H); 2.92-2.99 (m, 4H); 3.98-4.05 (m, 2H); 4.68 and 4.69 (2 s, 2H); 6.96 (dt, 1H, J=3.5, 1.1 Hz); 7.09-7.12 (m, 1H); 7.47 (dd, 1H, J=5.1, 1.0 Hz).

This is a diastereoisomer mixture in the ratio of approx. 2:3.

Step 3: 8-(Azetidin-1-yl)-8-(2-thienyl)-3-azaspiro[4.5]decan-2-one

A solution of 2-[4-(azetidin-1-yl)-1-(nitromethyl)-4-(2-thienyl)cyclohexyl]-acetic acid ethyl ester (3.90 g, 10.7 mmol) in ethanol (100 ml) was added to a mixture of iron powder (2.84 g, 53 mmol), ammonium chloride (14.2 g, 265 mmol) and water (10 ml) and the mixture was then stirred for 4 h at 80° C. The mixture was filtered and the residue was washed with ethanol. The filtrate was rendered alkaline by addition of 5% strength sodium bicarbonate solution (8 ml) and then concentrated i. vac. The crude product (6.30 g) was purified by flash chromatography (200 g, 20×5.7 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water). The mixture of non-polar and polar diastereoisomer isolated (1.60 g) was purified by medium pressure chromatography under 8-10 bar on a PuriFlash cartridge (PF-15SIHP, 40 g, 15 μm) and 2 PuriFlash cartridges (PF-15SIHP, 120 g, 15 μm) with methylene chloride/isopropanol (9:1) and 1% ammonia (25% in water).

Non-Polar Diastereoisomer

Yield: 504 mg (16%), white solid

Melting point: 180-183° C.

¹H-NMR (DMSO-d₆): 1.31-1.40 (m, 2H); 1.63-1.77 (m, 8H); 2.02 (s, 2H); 2.93 (s, 2H); 2.96 (t, 4H, J=6.9 Hz); 6.95 (d, 1H, J=3.5 Hz); 7.10 (dd, 1H, J=8.6, 3.5 Hz); 7.41 (br s, 1H); 7.46 (d, 1H, J=5.1 Hz).

Polar Diastereoisomer

Yield: 772 mg (25%), white solid

Melting point: 170-172° C.

¹H-NMR (DMSO-d₆): 1.30-1.40 (m, 2H); 1.62-1.82 (m, 8H); 1.93 (s, 2H); 2.96 (t, 4H, J=6.9 Hz); 3.03 (s, 2H); 6.95 (dd, 1H, J=3.5 Hz, 1.1 Hz); 7.10 (dd, 1H, J=5.1, 3.5 Hz); 7.45 (br s, 1H); 7.46 (dd, 2H, J=5.1 Hz, 1.0 Hz).

Step 4: 8-(Azetidin-1-yl)-8-(2-thienyl)-3-azaspiro[4.5]decane (polar diastereomer) (Example 427)

A solution of 8-(azetidin-1-yl)-8-(2-thienyl)-3-azaspiro[4.5]decan-2-one (polar diastereoisomer) (765 mg, 2.63 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise to a suspension of lithium aluminium hydride (500 mg, 13.1 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. under argon and the mixture was then stirred overnight at 60° C. After addition of water (500 μl), 1 N sodium hydroxide solution (1.3 ml) and water again (1.3 ml) the mixture was stirred for one hour at room temperature and thereafter filtered through sea sand and the filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 696 mg (96%), colourless oil

¹H-NMR (CDCl₃): 1.35 (ddd, 2H, J=13.1, 9.4, 3.7 Hz); 1.40-1.46 (m, 3H), 1.60-1.90 (m, 8H); 2.75 (s, 2H); 2.89 (t, 2H, J=7.1 Hz); 3.07 (t, 4H, J=7.0 Hz); 6.88 (dd, 1H, J=3.5, 1.1 Hz); 7.09 (dd, 1H, J=5.1, 3.5 Hz); 7.27 (dd, 1H, J=5.1, 1.1 Hz).

Example No. 414 8-(Azetidin-1-yl)-8-(2-thienyl)-3-azaspiro[4.5]decane (non-polar diastereomer) (Example no 428)

A solution of 8-(azetidin-1-yl)-8-(2-thienyl)-3-azaspiro[4.5]decan-2-one (non-polar diastereoisomer) (504 mg, 1.73 mmol) in anhydrous tetrahydrofuran (50 ml) was added dropwise to a suspension of lithium aluminium hydride (330 mg, 8.65 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. under argon and the mixture was then stirred overnight at 60° C. After addition of water (300 μl), 1 N sodium hydroxide solution (800 μl) and water again (800 μl) the mixture was stirred for 1 h at room temperature and thereafter was filtered through sea sand. The filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 414 mg (87%), oil

¹H-NMR (CDCl₃): 1.35 (ddd, 2H, J=13.4, 9.9, 3.7 Hz); 1.56-1.64 (m, 3H); 1.70-1.93 (m, 8H); 2.55 (s, 2H); 2.94 M. 2H, J=7.1 Hz); 3.08 (t, 4H, J=7.1 Hz); 6.87 (dd, 1H, J=3.5, 1.1 Hz); 7.08 (dd, 1H, J=5.1, 3.5 Hz); 7.27 (dd, 1H, J=5.1, 1.1 Hz).

Example No. 429 Step 1: (4-Azetidin-1-yl-4-phenylcyclohexylidene)acetic acid ethyl ester

Potassium tert-butylate (3.52 g, 31.4 mmol) was added to a solution of phosphonoacetic acid triethyl ester (7.03 g, 6.2 ml, 31.4 mmol) in anhydrous N,N-dimethylformamide (30 ml) under argon and the mixture was stirred for 10 min at room temperature. A solution of 4-(azetidin-1-yl)-4-phenylcyclohexanone (4.81 g, 21 mmol) in anhydrous N,N-dimethylformamide (60 ml) was then added to the mixture and the mixture was stirred for 1 h at room temperature and then poured into ice-water 80 g). The aqueous suspension was extracted with diethyl ether (4×40 ml). The combined organic extracts were dried with sodium sulfate and concentrated i. vac.

Yield: 6.30 g (100%), yellowish oil.

¹H-NMR (DMSO-d₆): 1.18 (t, 3H, J=7.1 Hz); 1.65 (quin, 2H, J=7.0 Hz); 1.75-1.90 (m, 2H); 1.96-2.10 (m, 3H); 2.73-2.82 (m, 2H); 2.88-2.96 (m, 1H); 2.90 (t, 4H, J=6.9 Hz); 4.05 (q, 2H, J=7.1 Hz); 5.62 (s, 1H); 7.23-7.45 (m, 5H).

Step 2: (4-Azetidin-1-yl-1-nitromethyl-4-phenylcyclohexyl)acetic acid ethyl ester

Nitromethane (1.65 g, 1.45 ml, 27.1 mmol) was added to a mixture of (4-azetidin-1-yl-4-phenylcyclohexylidene)acetic acid ethyl ester (6.30 g, 21 mmol) and tetra-n-butylammonium fluoride trihydrate (7.26 g, 23 mmol) in tetrahydrofuran (150 ml) and the mixture was stirred for 6 h at 70° C. and for 18 h at 45° C. Since the reaction was not complete, tetra-n-butylammonium fluoride trihydrate (2.42 g, 7.6 mmol) and nitromethane (550 mg, 483 μl, 9 mmol) were again added and the mixture was stirred for a further 5 h at 70° C. and for 18 h at 45° C. The reaction mixture was concentrated in vacuo and the residue (17.0 g) was purified by flash chromatography (200 g, 20×5.7 cm) with ethyl acetate/methanol (95:5).

Yield: 4.92 g (65%), brownish oil

¹H-NMR (DMSO-d₆): 1.10 and 1.18 (2 t, 3H, J=7.1 Hz); 1.30-1.42 (m, 2H); 1.62 (t, 2H, J=6.8 Hz); 1.70-1.80 (m, 4H); 1.85-1.95 (m, 2H); 2.36 (s, 1H); 2.84 (t, 4H, J=6.8 Hz); 3.95-4.08 (m, 2H); 4.63 and 4.73 (m, 2H); 7.26-7.45 (m, 5H).

LC-MS: m/z: [M+H]⁺=361.4, R_(t)=2.6 and 2.7 min.

A diastereoisomer mixture in the ratio of 4:3 is present.

Step 3: 8-Azetidin-1-yl-8-phenyl-2-azaspiro[4.5]decan-3-one

A solution of (4-azetidin-1-yl-1-nitromethyl-4-phenylcyclohexyl)acetic acid ethyl ester (4.92 g, 13.5 mmol) in ethanol (130 ml) was added to a mixture of iron powder (3.58 g, 67 mmol), ammonium chloride (17.9 g, 334 mmol) and water (13 ml) and the mixture was then stirred for 4 h at 80° C. and overnight at 65° C. The mixture was filtered and the residue on the filter was washed with ethanol. The filtrate was rendered alkaline by addition of 5% strength sodium bicarbonate solution (8 ml) and then concentrated i. vac. The residue (10.0 g) was purified by flash chromatography (400 g, 20×7.5 cm) with methylene chloride/methanol (95:5) and 1% ammonia (25% in water). The mixture of non-polar and polar diastereoisomer isolated (1.80 g) was purified by flash chromatography on two columns with PharmPrep (40-63 μm, 200 g, 20×5.7 cm) and the mixed fractions (670 mg) thereby obtained were purified on a PuriFlash cartridge (PF-15SIHP, 200 g, 15 μm) in each case with methylene chloride/ethanol (95:5) and 1% ammonia (25% in water).

Non-Polar Diastereoisomer

Yield: 719 mg (19%), white solid

Melting point: 180-187° C.

¹H-NMR (DMSO-d₆): 1.21-1.31 (m, 2H); 1.56-1.84 (m, 8H); 2.06 (s, 2H); 2.85 (t, 4H, J=6.8 Hz); 2.88 (s, 2H); 7.22-7.46 (m, 6H).

LC-MS: m/z: [M+H]⁺=285.4, R_(t)=1.9 min.

Polar Diastereoisomer

Yield: 907 mg (24%), white solid

Melting point: 150-155° C.

¹H-NMR (DMSO-d₆): 1.20-1.33 (m, 2H); 1.58-1.87 (m, 8H); 1.88 (s, 2H); 2.84 (t, 4H, J=6.8 Hz); 3.07 (s, 2H); 7.25-7.49 (m, 6H).

LC-MS: m/z: [M+H]⁺=285.4, R_(t)=1.8 min.

Step 4: 8-Azetidin-1-yl-8-phenyl-2-azaspiro[4.5]decane (polar diastereoisomer) (Example 429)

A solution of 8-azetidin-1-yl-8-phenyl)-2-azaspiro[4.5]decan-3-one (polar diastereoisomer) (892 mg, 3.14 mmol) in anhydrous tetrahydrofuran (80 ml) was added dropwise to a suspension of lithium aluminium hydride (599 mg, 15.7 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. under argon and the mixture was then stirred at 60° C. overnight. After addition of water (500 μl), 1 N sodium hydroxide solution (1.3 ml) and water again (1.3 ml) the mixture was stirred for one hour at room temperature and thereafter filtered through sea sand and the filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 830 mg (98%), colourless oil

¹H-NMR (DMSO-d₆): 1.12-1.22 (m, 2H); 1.23-1.30 (m, 2H); 1.52-1.66 (m, 4H); 1.70-1.81 (m, 3H); 2.53 (s, 2H); 2.70 (t, 2H, J=7.1 Hz); 2.82 (t, 4H, J=6.8 Hz); 3.34-3.42 (m, 2H); 7.24 (m, 3H); 7.37-7.43 (m, 2H).

LC-MS: m/z: [M+H]⁺=271.4, R_(t)=0.4 min.

Example No. 430 8-Azetidin-1-yl-8-phenyl-2-azaspiro[4.5]decane (non-polar diastereomer)

A solution of 8-azetidin-1-yl-8-phenyl)-3-azaspiro[4.5]decan-2-one (non-polar diastereoisomer) (701 mg, 2.46 mmol) in anhydrous tetrahydrofuran (100 ml) was added dropwise to a suspension of lithium aluminium hydride (470 mg, 12.3 mmol) in anhydrous tetrahydrofuran (20 ml) at 0° C. under argon and the mixture was then stirred at 60° C. overnight. After addition of water (500 μl), 1 N sodium hydroxide solution (1.3 ml) and water again (1.3 ml) the mixture was stirred for one hour at room temperature and thereafter filtered through sea sand and the filtrate was dried with sodium sulfate and concentrated i. vac.

Yield: 663 mg (95%), colourless oil

¹H-NMR (DMSO-d₆): 1.10-1.20 (m, 2H); 1.48 (t, 2H, J=7.0 Hz); 1.50-1.66 (m, 4H); 1.70 (m, 3H); 2.34 (s, 2H); 2.74 (t, 2H, J=7.0 Hz); 2.84 (t, 4H, J=6.8 Hz); 3.20-3.40 (m, 2H); 7.23-7.34 (m, 3H); 7.36-7.42 (m, 2H).

LC-MS: m/z: [M+H]⁺=271.4, R_(t)=0.2 min.

Example No. 431 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one (polar diastereomer)

Trifluoroacetic acid (5 ml) was added to a solution of 8-dimethylamino-3-oxo-8-phenyl-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (polar diastereoisomer) (1.28 g, 3.43 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated i. vac., the residue was dissolved in methylene chloride (50 ml) and the solution was washed with saturated sodium bicarbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Yield: 875 mg (94%), white solid

Melting point: 220-222° C.

¹H-NMR (CDCl₃): 1.34-1.44 (2H, m); 1.72-1.81 (2H, m); 1.86-2.02 (2M, br s); 2.04 (6H, s); 2.16-2.29 (2H, m); 2.30 (2H, s); 3.01 (2H, s); 5.60 (1M, s); 7.26-7.32 (3H, m); 7.36-7.41 (2H, m).

Example No. 432 and 433 Step 1: 8-Butyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one

A suspension of 8-(dimethylamino)-3-oxo-2-azaspiro[4.5]decane-8-carbonitrile (2.21 g, 10 mmol) in anhydrous tetrahydrofuran (140 ml) was added dropwise to a 2 M solution of n-butylmagnesium chloride in anhydrous tetrahydrofuran (20 ml, 40 mmol) at 0° C. under argon and the mixture was stirred for 20 h at room temperature. Saturated ammonium chloride solution (50 ml) was then added to the solution. The phases were separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated i. vac. The crude product (3.97 g) was taken up in methylene chloride and the suspension was washed with potassium carbonate solution. The organic phase was then dried with sodium sulfate and concentrated i. vac.

Yield: 1.88 g (75%), colourless oil which crystallized over time

¹H-NMR (CDCl₃): 0.90 and 0.91 (3H, 2 t, J=7.2 Hz); 1.14-1.47 (10H, m); 1.51-1.61 (2H, m); 1.87-1.82 (2H, m); 2.18 and 2.19 (2H, 2 s); 2.21 (s, 6H); 3.15 and 3.18 (2H, 2 s); 5.90 and 5.93 (1H, br s).

This is a diastereoisomer mixture in the ratio of approx. 1:1.

LC/MS: m/z: [M+H]⁺=253.3, R_(t)=1.3 min.

Step 2: 8-Butyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester (polar and non-polar diastereoisomer)

Di-tert-butyl dicarbonate (2.71 g. 12.4 mmol) and 4-dimethylaminopyridine (90 mg, 0.75 mmol) were added to a solution of 8-butyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (1.84 g, 7.3 mmol) in anhydrous acetonitrile (60 ml) and anhydrous tetrahydrofuran (20 ml). The reaction mixture was stirred for 72 h at 50° C. It was then concentrated i. vac. The residue was taken up in methylene chloride (100 ml) and the solution was washed with water (3×80 ml) and saturated sodium chloride solution (50 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (2.37 g) was purified by flash chromatography (220 g, 20×5.7 cm) with methylene chloride/methanol (95:5-9:1-4:1).

Non-Polar Diastereoisomer:

Yield: 819 mg (32%), orange-coloured solid

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.1 Hz); 1.17-1.40 (10H, m); 1.51 (9H, s); 1.54-1.76 (4H, m); 2.21 (6H, s); 2.39 (2H, s); 3.49 (2M, s).

Polar Diastereoisomer:

Yield: 647 mg (25%), yellow oil

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.1 Hz); 1.22-1.48 (10H, m); 1.53 (9H, s); 1.58-1.76 (4H, m); 2.25 (6M, s); 2.39 (2H, s); 3.52 (2H, s).

Mixed Fraction:

Yield: 310 mg (12%), yellow oil

Step 3: 8-Butyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (polar diastereoisomer) (Example No. 432)

Trifluoroacetic acid (12.5 ml) was added to a solution of 8-butyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester—polar diastereoisomer (603 mg, 1.71 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 4 h at room temperature. The reaction mixture was then concentrated i. vac., the residue was taken up in methylene chloride (50 ml) and the solution was washed with 25% strength potassium carbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Polar Diastereoisomer:

Yield: 365 mg (85%), yellowish solid

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.2 Hz); 1.11-1.48 (10H, m); 1.53-1.64 (2H, m); 1.69-1.79 (2M, m); 2.17 (2M, s); 2.21 (6M, s); 3.17 (2M, s); 6.10 (br s, 1H).

¹³C-NMR (CDCl₃): 14.1; 23.7; 26.5; 28.3; 30.7 (2C); 31.9 (2C); 37.3 (2C); 39.0; 44.0; 52.6; 56.2; 177.9.

Step 4: 8-Butyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one (non-polar diastereoisomer) (Example No. 433)

Trifluoroacetic acid (12.5 ml) was added to a solution of 8-butyl-8-dimethylamino-3-oxo-2-azaspiro[4.5]decane-2-carboxylic acid tert-butyl ester—non-polar diastereoisomer (740 mg, 2.09 mmol) in anhydrous methylene chloride (50 ml) and the mixture was stirred for 2 h at room temperature. The reaction mixture was then concentrated i. vac., the residue was taken up in methylene chloride (50 ml) and the solution was washed with 25% strength potassium carbonate solution (3×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac.

Non-Polar Diastereoisomer:

Yield: 416 mg (79%), yellow solid.

¹H-NMR (CDCl₃): 0.90 (3H, t, J=7.2 Hz); 1.16-1.43 (10H, m); 1.58-1.78 (4H, m); 2.19 (2M, s); 2.22 (6H, s); 3.14 (2H, s); 5.97 (br s, 1H).

¹³C-NMR (CDCl₃): 14.1; 23.8; 26.6; 28.6; 30.6 (2C); 31.8 (2C); 37.3 (2C); 39.1; 42.1; 54.6; 177.7.

In accordance with the general synthesis instructions described and analogously to the concrete synthesis examples given by way of example, the following examples were prepared from the polar and non-polar precursors (8-benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one, (8-benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine, 8-dimethylamino-8-phenyl-3-azaspiro[4.5]decan-4-one, 8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one, 8-butyl-8-dimethylamino-3-azaspiro[4.5]decan-4-one, 8-dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one, dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine, 8-(dimethylamino)-8-thiophen-2-yl-2-azaspiro[4.5]decan-3-one, 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-4-one, dimethyl-[8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-amine, dimethyl-(8-phenyl-3-azaspiro[4.5]decan-8-yl)-amine, 8-(cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one, 8-(cyclopentylmethyl)-N,N-dimethyl-2-azaspiro[4.5]decan-8-amine, 8-cyclopentyl-N,N-dimethyl-2-azaspiro[4.5]decan-8-amine, 8-(azetidin-1-yl)-8-(thiophen-2-yl)-2-azaspiro[4.5]decane, 8-(azetidin-1-yl)-8-phenyl-2-azaspiro[4.5]decane, 8-(5-chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one, 8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one) by acylation, arylation, alkylation, reductive amination or reduction of amides.

Ex. Building LC-MS no. Diastereomer* Block/Method/Yield [M + H]⁺/R_(t) NMR spectrum 36 1 Ex. no. 31/ [M + H]⁺ = 361.2, ¹H-NMR (CDCl₃): 1.37 (2 H, m); 1.53-1.65 (4 H, m); 1.81-1.93 (4 H, Acylation/ R_(t) = 3.3 min. m); 2.10 (9 H, m); 2.29 (2 H, m); 2.44 (3 H, s); 3.14 (2 H, m); 3.32 (2 19% H, m); 3.43 (2 H, t); 6.60 (2 H, m). 37 1 Ex. no. 31/ [M + H]⁺ = 347.1, ¹H-NMR (CDCl₃): 0.73 (2 H, m); 0.98 (2 H, m); 1.40-1.46 (2 H, m); Acylation/ R_(t) = 2.7 min. 1.56-1.73 (5 H, m); 1.89 (2 H, m); 2.09 (4 H, s); 2.12 (4 H, s); 2.45 (3 18% H, s); 3.35 (1 H, s); 3.49 (3 H, t); 3.62 (1 H, t); 6.65 (2 H, m). 38 1 Ex. no. 31/ [M + H]⁺ = 349.2, ¹H-NMR (CDCl₃): 1.10 (6 H, d); 1.37-1.44 (2 H, m); 1.57-1.71 (4 H, Acylation/ R_(t) = 2.9 min. m); 1.80-1.94 (2 H, m); 2.01 (1 H, m); 2.11 (7 H, m); 2.45 (3 H, s); 18% 2.59 (1 H, m); 3.33 (2 H, m); 3.45 (2 H, m); 6.64 (2 H, m). 39 1 Ex. no. 31/ [M + H]⁺ = 363.2, ¹H-NMR (DMSO-d₆): 0.94 (6 H, m); 1.40 (2 H, m); 1.56-1.69 (4 H, Acylation/ R_(t) = 3.3 min. m); 1.95 (2 H, m); 2.05 (3 H, m); 2.12 (8 H, m); 2.45 (3 H, s); 3.30 (1 28% H, s); 3.35 (1 H, s); 3.45 (2 H, m); 6.62 (1 H, m); 6.67 (1 H, m). 40 1 Ex. no. 31/ [M + H]⁺ = 335.2, ¹H-NMR (CDCl₃): 1.12 (3 H, t); 1.39 (2 H, m); 1.58 (4 H, m); 1.84 (2 Acylation/ R_(t) = 2.7 min H, m); 2.06 (4 H, s); 2.09 (4 H, s); 2.22 (2 H, m); 2.43 (3 H, s); 3.25 27% (1 H, s); 3.33 (1 H, s); 3.40 (2 H, m); 6.62 (2 H, m). 42 1 Ex. no. 18/ [M + H]⁺ = 337.2, ¹H-NMR (CDCl₃): 1.39 (2 H, m); 1.60-1.70 (4 H, m); 1.94 (2 H, m); Acylation/ R_(t) = 2.0 min 2.09 (7 H, m); 2.15 (1 H, b s); 3.28 (1 H, s); 3.42 (5 H, m); 3.51 (1 H, 90% s); 3.99 (2 H, s); 6.84 (1 H, s); 7.03 (1 H, s); 7.22 (1 H, s). 43 1 Ex. no. 18/ [M + H]⁺ = 347.2, ¹H-NMR (CDCl₃): 1.32 (2 H, m); 1.52 (1 H, t); 1.58 (3 H, t); 1.62-1.93 Acylation/ R_(t) = 1.8 mm (4 H, m); 2.00-2.12 (10 H, m); 2.29 (2 H, m); 3.09 (2 H, m); 3.28 (1 88% H, m); 3.38 (1 H, t); 6.77 (1 H, m); 6.97 (1 H, m); 7.16 (1 H, m). 44 1 Ex. no. 18/ [M + H]⁺ = 333.2, ¹H-NMR (CDCl₃): 0.73 (2 H, m); 0.98 (2 H, m); 1.40-1.75 (6 H, b m); Acylation/ R_(t) = 2.4 mm 1.94 (2 H, b s); 2.09 (2 H, s); 2.12 (4 H, s); 2.20 (2 H, b s); 3.38 (1 H, 37% s); 3.49 (2 H, m); 3.64 (1 H, t); 6.86 (1 H, m); 7.04 (1 H, m); 7.27 (1 H, m). 45 1 Ex. no. 18/ [M + H]⁺ = 335.2, ¹H-NMR (CDCl₃): 1.04 (6 H, m); 1.35 (2 H, m); 1.53 (1 H, t); 1.63 (3 Acylation/ R_(t) = 2.0 min H, m); 1.88 (2 H, m); 2.03 (6 H, m); 2.11 (2 H, m); 2.55 (1 H, m); 57% 3.28 (2 H, m); 3.41 (2 H, m); 6.78 (1 H, m); 6.97 (1 H, m); 7.16 (1 H, m). 46 1 Ex. no. 18/ [M + H]⁺ = 349.2, ¹H-NMR (DMSO-d₆): 0.93 (6 H, m); 1.37 (2 H, m); 1.56 (1 H, t); 1.63 Acylation/ R_(t) = 2.2 min (3 H, m); 1.89 (2 H, m); 2.01-2.17 (11 H, b m); 3.27 (1 H, s); 3.33 (1 51% H, s); 3.41 (2 H, m); 6.08 (1 H, m); 6.97 (1 H, m); 7.18 (1 H, m). 47 1 Ex. no. 70/ [M + H]⁺ = 323.2, ¹H-NMR (CDCl₃): 1.36 (2 H, m); 1.50 (2 H, t); 1.68 (2 H, m); 1.89 (2 Reduction/ R_(t) = 0.5 min H, m); 2.08 (8 H, s); 2.46 (2 H, s); 2.54 (2 H, t); 2.60 (2 H, t); 3.33 (3 90% H, s); 3.46 (2 H, t); 6.82 (1 H, m); 7.01 (1 H, m); 7.20 (1 H, m). 49 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (DMSO-d₆): 0.10-0.15 (2 H, m); 0.43-0.50 (2 H, m); 0.82- Reductive 274.3 (100%) 0.92 (1 H, m); 1.27-1.35 (2 H, m); 1.52 (2 H, t, J = 6.8 Hz); 1.62- amination/ [M + H]⁺ = 319.3 1.71 (2 H, m); 1.82-2.01 (4 H, m); 1.99 (6 H, s); 2.30-2.45 (2 H, m); 69% (40%), R_(t) = 0.4 2.51-2.56 (2 H m); 2.63-2.72 (2 H, m); 6.92 (1 H, dd, J = 3.5 and min. 1.1 Hz); 7.05 (1 H dd, J = 5.1 and 3.5 Hz); 7.41 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (DMSO-d₆): 3.6; 8.7; 32.7; 33.0; 36.0; 37.7; 40.5; 41.3; 41.6; 52.9; 58.6; 59.9; 65.0; 123.5; 124.7; 126.3; 143.2. 50 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.32-1.44 (2 H, m); 1.59 (1 H, t, J = 7.1 Hz); 1.62- Acylation/ 316.3 (100%) 1.75 (5 H, m); 1.77-2.01 (4 H, m); 2.02-2.24 (4 H, m); 2.11 (6 H, s); 48% [M + H]⁺ = 361.4 2.33-2.38 (2 H, m); 2.66-2.78 (1 H, m); 3.29 (1.2 H, s); 3.34 (0.8 H, (65%), R_(t) = 3.0 s); 3.42 (0.8 H, t, J = 7.6 Hz); 3.45 (1.2 H, t, J = 7.8 Hz); 6.82-6.86 min. (1 H, m); 7.00-7.06 (1 H, m); 7.20-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 18.71; 18.74; 28.5; 28.6; 31.1; 31.2; 32.3; 32.8; 33.5; 35.6; 37.0; 38.08; 38.09; 40.1; 41.2; 41.7; 42.0; 43.7; 45.1; 53.4; 55.3; 56.5; 59.8; 123.3; 123.5; 124.8; 125.1; 126.1; 126.3; 142.1; 143.7; 171.0; 171.1. 51 1 Ex. no. 48/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.01-0.06 (2 H, m); 0.38-0.44 (2 H, m); 0.59-0.72 Reduction/ 288.3 (100%) (1 H, m); 1.34-1.43 (4 H, m); 1.52 (2 H, t, J = 6.8 Hz); 1.66-1.74 (2 55% [M+H]⁺ = 333.4 H, m); 1.84-1.99 (2 H, m); 2.05-2.18 (2 H, m); 2.10 (6 H, s); 2.45 (2 (25%), R_(t) = 0.7 H, s); 2.47-2.57 (4 H, m); 6.84 (1 H, dd, J = 3.6 and 1.1 Hz); 7.03 (1 min.h H, dd, J = 5.1 and 3.6 Hz); 7.22 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 4.3; 9.1; 33.7; 34.3; 38.2; 40.9; 54.0; 56.9; 59.6; 65.5; 123.2; 125.0; 126.2. 52 1 Ex. no. 50/ MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.38 (2 H, ddd, J = 13.3, 10.0 and 3.5 Hz); 1.50 (2 Reduction/ 302.3 (100%) H, t, J = 6.8 Hz); 1.54-1.64 (4 H, m); 1.65-1.73 (2 H, m); 1.78-1.96 65% [M + H]⁺ = 347.4 (4 H, m); 1.98-2.16 (4 H, m); 2.10 (6 H, s); 2.20-2.30 (3 H, m); 2.41 (25%), R_(t) = 1.9 (2 H, s); 2.49 (2 H, t, J = 6.8 Hz); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); mm 7.03 (1 H, dd, J = 5.1 and 3.6 Hz); 7.22 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 18.7; 28.4; 33.7; 34.5; 36.1; 38.2; 40.8; 54.0; 54.8; 59.6; 65.8; 123.2; 124.9; 126.1. 53 1 Ex. no. 43/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.38-1.48 (2 H, m); 1.60-1.82 (8 H, m); 1.85-1.94 Reduction/ 288.3 (100%) (1 H, m); 1.94-2.04 (2 H, m); 2.06-2.18 (4 H, m); 2.12 (6 H, s); 60% [M + H]⁺ = 333.4 2.55-2.95 (6 H, m); 6.85 (1 H, br d, J = 3.0 Hz); 7.03 (1 H, dd, J = (20%), R_(t) = 1.1 5.1 and 3.6 Hz); 7.22-7.24 (1 H, dd, J = 5.0 and 0.8 Hz). mm ¹³C-NMR (CDCl₃): 18.7; 27.8; 30.3; 33.3; 33.6; 36.9; 38.1; 41.1; 53.5; 59.9; 62.2; 64.4; 123.6; 125.3; 126.3. 54 1 Ex. no. 18/ [M + H]⁺ = 363.3, ¹H-NMR (CDCl₃): 0.91 (6 H, t, J = 6.1 Hz); 1.34-1.45 (2 H, m); 1.50- Acylation/ R_(t) = 3.1 min 1.73 (8 H, m); 1.80-2.08 (2 H, m); 2.09 and 2.11 (6 H, 2 s); 2.15- 55% 2.26 (3 H, m); 3.30 (1.2 H, s); 3.36 (0.8 H, s); 3.41-3.50 (2 H, m); 6.83-6.87 (1 H, m); 7.01-7.07 (1 H, m); 7.23-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 22.3; 22.38; 22.41; 27.9; 28.0; 31.1; 31.2; 32.4; 32.8; 33.4; 33.7; 33.8; 35.6; 37.2; 38.1; 40.1; 42.0; 44.0; 45.0; 55.5; 56.5; 59.9; 123.3; 123.5; 124.8; 125.0; 126.1; 126.3; 172.17; 172.2. 55 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.38-1.46 (2 H, m); 1.60 and 1.61 (6 H, 2 s); 1.65 Acylation/ 315.2 (100%) (2 H, t, J = 7.4 Hz); 1.68-1.81 (3 H, m); 1.93-2.09 (3 H, m); 2.10 36% [M + H]⁺ = 360.2 and 2.11 (6 H, 2 s); 3.43 (0.7 H, s); 3.63 (1.3 H, 3 s); 3.55 (1.3 H, t, (10%), R_(t) = 2.6 J = 7.5 Hz); 3.83 (0.7 H, t, J = 7.0 Hz); 6.85 (1 H, dd, J = 3.5 and 0.9 min Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 25.07; 25.1; 30.4; 31.2; 33.0; 33.1; 34.0; 36.7; 38.0; 38.1; 39.2; 43.0; 46.2; 46.4; 57.9; 59.8; 121.7; 121.8; 123.4; 124.8; 124.9; 126.2; 126.3; 165.9. 56 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.33-1.45 (2 H, m); 1.50-1.74 (5 H, m); 1.76-2.06 Acylation/ 332.2 (100%) (3 H, m); 2.09 and 2.10 (6 H, 2 s); 2.12-2.40 (2 H, m); 2.30-2.40 (2 50% [M + H]⁺ = 377.3 H, m); 2.66-2.76 (1 H, m); 3.28 (1.2 H, s); 3.36 (0.8 H, s); 3.40-3.50 (50%), R_(t) = 2.5 (3 H, m); 3.70-3.78 (1 H, m); 3.82-3.89 (1 H, m); 3.93-4.00 (1 H, min. m); 6.84 (1 H, dt, J = 3.7 and 1.1 Hz); 7.01-7.06 (1 H, m); 7.22 (0.4 H, dd, J = 5.1 and 1.1 Hz); 7.24 (0.6 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 31.1; 31.2; 32.3; 32.83; 32.85; 33.4; 35.3; 35.5; 37.0; 38.1; 38.5; 40.1; 42.1; 43.9; 45.1; 55.4; 56.4; 59.8; 67.6; 73.31; 73.33; 123.3; 123.5; 124.8; 125.1; 126.1; 126.3; 143.6; 170.40; 170.44. 57 1 Ex. no. 18/ [M + H]⁺ = 349.3, ¹H-NMR (CDCl₃): 1.33-1.44 (2 H, m); 1.60-1.72 (5 H, m); 1.85-2.08 Acylation/ R_(t) = 2.3 min. (2 H, m); 2.09 and 2.11 (6 H, 2 s); 2.11-2.18 (1 H, m); 3.06 (1.2 H, 41% s); 3.23 (0.8 H, t, J = 7.2 Hz); 3.40 (0.8 H, s); 3.52 (1.2 H, t, J = 7.2 Hz); 3.87-3.98 (1 H, m); 4.74-4.81 (2 H, m); 4.90-4.96 (2 H, m); 6.83-6.86 (1 H, m); 7.01-7.06 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 30.9; 31.2; 32.9; 32.3; 35.0; 36.9; 38.04; 38.09; 38.3; 38.5; 40.1; 42.1; 44.2; 44.3; 55.6; 55.9; 59.8; 73.01; 73.03; 123.4; 123.5; 124.9; 125.0; 126.2; 126.3; 169.6; 169.7. 58 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.38-1.54 (4 H, m); 1.55-1.81 (8 H, m); 1.95-2.08 Acylation/ 313.2 (100%) (2 H, m); 2.10 and 2.12 (6 H, 2 s); 3.38 (0.8 H, s); 3.50 (1.2 H, t, J = 23% [M + H]⁺ = 358.2 7.3 Hz); 3.71 (1.2 H, s); 3.90 (0.8 H, t, J = 1.1 Hz); 6.86 (1 H, br d, (6%), R_(t) = 2.6 J = 3.5 Hz); 7.03-7.07 (1 H, m); 7.23-7.26 (1 H, m). min. ¹³C-NMR (CDCl₃): 16.3; 16.7; 30.7; 31.1; 33.2; 38.07; 38.1; 39.9; 42.5; 45.7; 46.1; 120.3; 123.4; 124.9; 126.2; 126.3; 163.0. 59 1 Ex. no. 18/ [M + H]⁺ = 393.3, ¹H-NMR (CDCl₃): 1.15 (2.4 H, s); 1.16 (3.6 H, s); 1.30-1.46 (2 H, m); Acylation/ R_(t) = 2.8 min. 1.60 (1.2 H, t, J = 7.2 Hz); 1.63-1.74 (2.8 H, m); 1.80-2.02 (4 H, m); 84% 2.04-2.22 (8 H, m); 2.23-2.30 (2 H, m); 3.16 (1.2 H, s); 3.18 (1.8 H, s); 3.32 (1.2 H, s); 3.36 (0.8 H, s); 3.44-3.50 (2 H, m); 6.83-6.87 (1 H, m); 7.01-7.07 (1 H, m); 7.21-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 24.7; 25.0; 28.7; 29.1; 31.0; 31.1; 32.7; 33.4; 34.0; 34.2; 35.6; 37.1; 38.1; 40.0; 42.0; 44.0; 45.0; 49.1; 53.4; 55.5; 56.4; 59.8; 73.90; 73.94; 123.2; 124.7; 126.0; 126.2; 171.91; 171.94. 60 1 Ex. no. 18/ [M + H]⁺ = 377.3, ¹H-NMR (CDCl₃): 1.34-1.46 (2 H, m); 1.56-1.74 (7 H, m); 1.84-2.02 Acylation/ R_(t) = 2.5 min. (4 H, m); 2.09 and 2.12 (6 H, 2 s); 2.16-2.26 (1 H, m); 2.52-2.61 (1 57% H, m); 3.34-3.54 (6 H, m); 3.99-4.05 (2 H, m); 6.83-6.87 (1 H, m); 7.01-7.07 (1 H, m); 7.21-7.27 (1 H, m). ¹³C-NMR (CDCl₃): 28.58; 28.6; 31.0; 31.2; 32.8; 33.4; 35.5; 37.1; 38.1; 39.6; 39.8; 39.9; 42.0; 44.2; 44.7; 55.6; 56.0; 59.8; 67.3; 123.3; 123.6; 124.8; 125.1; 126.1; 126.4; 173.0; 173.1. 61 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.37-1.46 (2 H, m); 1.63-1.78 (4 H, m); 1.93-2.09 Acylation/ 327.2 (100%) (4 H, m); 2.10 (6 H, s); 2.12-2.15 (1 H, m); 2.20-2.33 (1 H, m); 68% [M + H]⁺ = 372.3 2.53-2.68 (2 H, m); 2.72-2.82 (2 H, m); 3.35 (1.2 H, s); 3.42 (0.8 H, (5%), R_(t) = 2.7 s); 3.51-3.57 (2 H, m); 6.85 (1 H, dd, J = 3.5 and 0.9 Hz); 7.04 (1 H, min. td, J = 5.1 and 3.6 Hz); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 16.5; 30.5; 30.6; 31.2; 33.0; 33.1; 34.4; 37.2; 38.0; 38.1; 38.8; 39.0; 39.8; 42.7; 44.9; 45.5; 56.7; 57.1; 59.8; 120.8; 120.9; 123.4; 124.9; 126.2; 126.3, 164.4; 164.7. 62 1 Ex. no. 18/ [M + H]⁺ = 361.3, ¹H-NMR (CDCl₃): 0.03-0.08 (2 H, m); 0.38-0.45 (2 H, m); 0.66-0.76 Acylation/ R_(t) = 3.0 min. (1 H, m); 1.34-1.45 (2 H, m); 1.50-1.64 (3 H, m); 1.64-1.72 (3 H, 61% m); 1.85-2.02 (3 H, m); 2.03 and 2.12 (6 H, 2 s); 2.14-2.25 (1 H, m); 2.31-2.38 (2 H, m); 3.32 (1.2 H, s); 3.36 (0.8 H, s); 3.34-3.50 (2 H, m); 6.83-6.87 (1 H, m); 7.01-7.07 (1 H, m); 7.21-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 4.5; 10.7; 28.5; 30.12; 30.15; 31.1; 31.2; 32.8; 33.4; 34.4; 34.8; 35.6; 37.1; 38.1; 40.1; 42.0; 43.9; 45.0; 55.3; 56.5, 59.9; 123.3; 123.5; 124.9; 125.1; 126.1; 126.3; 143.6; 171.87; 171.9. 63 1 Ex. no. 18/ [M + H]⁺ = 365.3, ¹H-NMR (CDCl₃): 1.35-1.44 (8 H, m); 1.53-1.58 (1 H, m); 1.64-1.75 Acylation/ R_(t) = 2.5 min. (3 H, m); 1.95-2.09 (3 H, m); 2.10 and 2.11 (6 H, 2 s); 2.12-2.18 (1 67% H, m); 3.18 and 3.19 (3 H, 2 s); 3.42 (0.7 H, s); 3.57 (1.3 H, t, J = 7.4 Hz); 3.62 (1.3 H, s); 3.73 (0.7 H, t, J = 7.0 Hz); 6.85 (1 H, dd, J = 3.5 and 0.7 Hz); 7.04 (1 H, dd, J = 5.0 and 3.6 Hz); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 24.1; 30.3; 30.6; 31.4; 32.9; 33.1; 34.0; 38.07; 38.1; 38.8; 42.4; 45.4; 45.8; 51.57; 51.59; 56.8; 57.7; 59.9; 79.5; 79.8; 123.3; 124.8; 126.1; 126.3; 172.6; 172.9. 64 1 Ex. no. 18/ [M + H]⁺ = 377.3, ¹H-NMR (CDCl₃): 1.34-1.45 (2 H, m); 1.51-1.73 (6 H, m); 1.84-2.00 Acylation/ R_(t) = 2.7 min. (4 H, m); 2.09 and 2.11 (6 H, 2 s); 2.13-2.23 (2 H, m); 2.34-2.43 (1 58% H, m); 2.57-2.65 (1 H, m); 3.28-3.40 (2 H, m); 3.40-3.55 (2 H, m); 3.70-3.77 (1 H, m); 3.82-3.90 (1 H, m); 4.25-4.32 (1 H, m); 6.84- 6.86 (1 H, m); 7.01-7.07 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 25.63; 25.66; 31.1; 31.15; 31.2; 31.5; 31.6, 32.8; 32.9; 33.3; 38.1; 40.1; 40.5; 40.9; 42.0; 43.9; 45.2; 55.4; 56.6; 59.9; 67.81; 67.84; 75.99; 76.0; 123.3; 124.8; 126.1; 126.3; 169.5; 169.6. 65 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.22 (2.6 H, s); 1.23 (3.4 H, s); 1.32-4.47 (2 H, m); Acylation/ 334.3, R_(t) = 2.5 1.57-1.74 (4 H, m); 1.83 (2 H, t, J = 6.8 Hz); 1.87-2.02 (2 H, m); 28% min. 2.02-2.24 (2 H, m); 2.08 (2.6 H, s); 2.11 (3.4 H, s); 2.36-2.44 (2 H, m); 3.32 (1.2 H, s); 3.36 (0.8 H, s); 3.43-3.50 (2 H, m); 6.84 (0.4 H, dd, J = 3.6 and 1.1 Hz); 6.85 (0.6 H, dd, J = 3.6 and 1.1 Hz); 7.02 (0.4 H, dd, J = 5.1 and 3.6 Hz); 7.05 (0.6 H, dd, J = 5.1 and 3.6 Hz); 7.23 (0.4 H, dd, J = 5.1 and 1.1 Hz); 7.25 (0.6 H, dd, J = 5.1 and 1.1 Hz). The OH signal could not be identified. ¹³C-NMR (CDCl₃): 29.1; 29.4; 29.5; 31.1; 31.2; 32.7; 33.4; 35.5; 37.2; 38.1; 40.0; 42.1; 44.1; 45.2; 55.7; 56.7; 59.7; 69.51; 69.55; 123.2; 123.4; 124.7; 125.1; 126.0; 126.2; 172.6; 172.7. 66 1 Ex. no. 18/ [M + H]⁺ = 363.2 ¹H-NMR (DMSO-d₆): 1.22-1.32 (2 H, m); 1.41-1.48 (1 H, m); 1.52- Acylation/ (4%) 1.66 (6 H, m); 1.68-1.77 (1 H, m); 1.99 (4 H, s); 2.00 (2 H, s); 1.94- 50% [MH − NHMe₂]⁺ = 2.06 (4 H, m, overlapped); 2.45-2.52 (2 H, m, overlapped by the 318.3 (100%), DMSO signal); 3.17 (0.8 H, s); 3.32 (1.2 H; t, J = 7.1 Hz, overlapped R_(t) = 2.6 min. by the water signal); 3.35 (1.2 H; s); 3.54 (0.8 H; t, J = 7.1 Hz); 5.747 (0.3 H, s); 5.754 (0.7 H, s); 6.92-6.94 (1 H, m); 7.04-7.07 (1 H, m); 7.40-7.42 (1 H, m). ¹³C-NMR (DMSO-d₆): 12.2; 29.9; 30.0; 30.7; 32.4; 32.5; 33.4; 33.6; 37.7; 38.7; 41.5; 44.4; 44.5; 54.8; 59.0; 59.1; 75.2; 75.5; 123.6; 124.8; 124.9; 126.3; 171.1; 171.2. 67 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.95-1.02 (2 H, m); 1.32-1.37 (2 H, m); 1.37-1.46 Acylation/ 327.2 (100%) (2 H, m); 1.61-1.75 (4 H, m); 1.87-2.06 (3 H, m); 2.10 (2.5 H, s); 30% [M + H]⁺ = 372.3 2.11 (3.5 H, s); 2.13-2.22 (1 H, m); 2.45 (2 H, s); 3.29 (1.1 H, s); (98%), R_(t) = 2.5 3.39 (0.9 H, s); 3.46 (0.9 H, t, J = 7.1 Hz); 3.52 (1.1 H, t, J = 7.3 Hz); min. 6.83-6.86 (1 H, m); 7.02 (0.5 H, dd, J = 5.1 and 3.6 Hz); 7.04 (0.5 H, dd, J = 5.1 and 3.6 Hz); 7.22 (0.5 H, dd, J = 5.1 and 1.1 Hz); 7.24 (0.5 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 6.6; 6.7; 14.0; 31.0; 31.1; 32.8; 33.3; 35.4; 36.9; 38.1; 38.1; 39.3; 39.7; 40.1; 42.3; 44.2; 45.2; 55.6; 58.5; 59.8; 59.8; 123.1; 123.2; 123.3; 123.6; 124.8; 125.1; 126.1; 126.3; 143.5; 167.2; 167.2. 68 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.34-1.46 (2 H, m); 1.60-1.75 (4 H, m); 1.85-2.06 Acylation/ 341.2 (95%) (4 H, m); 2.08 (2.5 H, s); 2.11 (3.5 H, s); 2.16-2.30 (4 H, m); 2.58- 44% [M + H]⁺ = 386.3 2.67 (2 H, m); 2.69 (0.8 H, s); 2.70 (1.2 H, s); 3.30 (1.2 H, s); 3.37 (100%), R_(t) = 2.7 (0.8 H, s); 3.45 (0.8 H, t, J = 7.1 Hz); 3.50 (1.2 H, t, J = 7.3 Hz); 6.84 min. (0.4 H, dd, J = 3.6 and 1.1 Hz); 6.86 (0.6 H, dd, J = 3.5 and 1.0 Hz); 7.02 (0.4 H, dd, J = 5.1 and 3.6 Hz); 7.05 (0.6 H, dd, J = 5.1 and 3.6 Hz); 7.23 (0.4 H, dd, J = 5.1 and 1.1 Hz); 7.25 (0.6 H, dd, J = 5.1 and 1.1 Hz). 69 1 Ex. no. 18/ [M + H]⁺ = 375.3, ¹H-NMR (CDCl₃): 1.35-1.45 (2 H, m); 1.46-1.76 (10 H, m); 1.78- Acylation/ R_(t) = 3.2 min. 1.96 (3 H, m); 1.96-2.09 (3 H, m); 2.09 and 2.11 (6 H, 2 s); 2.16- 32% 2.32 (3 H, m); 3.29 (1.2 H, s); 3.36 (0.8 H, s); 3.40-3.50 (2 H, m); 6.83-6.87 (1 H, m); 7.01-7.09 (1 H, m); 7.21-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 18.2; 18.29; 18.30; 27.8; 27.9; 27.96; 28.0; 31.1; 31.2; 31.5; 31.7; 31.97; 31.99; 32.04; 32.5; 32.8; 33.4; 35.2; 35.5; 35.7; 35.73; 37.1; 38.1; 40.1; 42.0; 43.9; 45.0; 55.4; 56.4; 59.9; 77.2; 77.5; 123.3; 123.5; 124.9; 125.1; 126.1; 126.3; 171.9; 172.0. 70 1 Ex. no. 57/ [M + H]⁺ = 335.3, ¹H-NMR (CDCl₃): 1.32-1.40 (2 H, m); 1.48 (2 H, t, J = 6.9 Hz); 1.63- Reduction/ R_(t) = 0.2 min. 1.71 (2 H, m); 1.75-2.00 (3 H, m); 2.00-2.08 (1 H, m); 2.09 (6 H, s); 44% 2.35 (2 H, s); 2.46 (2 H, t, J = 6.9 Hz); 2.73 (2 H, d, J = 7.3 Hz); 3.13-3.22 (1 H, m); 4.42 (2 H, t, J = 6.2 Hz); 4.78 (2 H, dd, J = 7.8 and 6.0 Hz); 6.84 (1 H, d, J = 3.5 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, d, J = 5.1 Hz). ¹³C-NMR (CDCl₃): 19.8; 33.6; 34.3; 34.7; 38.1; 41.0; 53.8; 59.6; 59.8; 65.7; 76.5; 123.2; 124.9; 126.1. 71 1 Ex. no. 13/ [M + H]⁺ = 259.2, ¹H-NMR (CDCl₃): 1.31 (2 H, m); 1.43 (2 H, m); 1.63 (2 H, m); 1.91 (2 Reduction/ R_(t) = 0.6 min H, m); 2.03 (6 H, s); 2.24 (2 H, m); 2.84 (2 H, s); 2.95 (2 H, m); 7.25- 77% 7.39 (5 H, m). 72 1 Ex. no. 71/ [M + H]⁺ = 329.4, ¹H-NMR (CDCl₃): 0.97 (t, 3H, J = 7.4 Hz); 1.23-1.35 (m, 2H); 1.52- Acylation/ R_(t) = 2.8 min. 1.74 (m, 8H); 2.02 and 2.04 (2 s, 6H); 2.18-2.28 (m, 3H); 2.23-2.41 86% (br s, 1 H); 3.34 and 3.41 (2 s, 2H); 3.39-3.48 (m, 2H); 7.23-7.42 (m, 5H). ¹³C-NMR (CDCl₃): 13.7; 14.0; 18.4; 18.5; 18.9; 30.1; 30.9; 31.2; 31.5; 36.4; 36.9; 37.8; 38.0; 38.1; 40.3; 42.3; 43.9; 45.0; 55.1; 56.4; 60.8; 126.5; 126.7; 127.6; 127.63; 127.67; 127.7; 171.9; 172.0. 73 1 Ex. no. 71/ [M + H]⁺ = 301.2, ¹H-NMR (CDCl₃): 1.30 (2 H, m); 1.54 (1 H, m); 1.62 (3 H, m); 1.83- Acylation/ R_(t) = 1.5 min 1.96 (2 H, m); 2.00-2.03 (9 H, m); 2.19 (1 H, m); 2.32 (1 H, m); 3.32- 56% 3.45 (4 H, m); 7.23-7.39 (5 H, m). 74 1 Ex. no. 71/ [M + H]⁺ = 315.3, ¹H-NMR (CDCl₃): 0.90 (3 H, t); 1.30 (4 H, m); 1.44 (4 H, m); 1.66 (2 Reductive R_(t) = 1.4 min H, m); 1.85 (2 H, m); 2.02 (6 H, s); 2.26 (2 H, m); 2.37 (2 H, m); 2.46 amination/ (4 H, m); 7.29 (5 H, m). 83% 75 1 Ex. no. 71/ [M + H]⁺ = 371.4, ¹H-NMR (CDCl₃): 1.23-1.34 (2 H, m); 1.51-1.70 (5 H, m); 1.83-1.98 Acylation/ R_(t) = 2.8 min. (4 H, m); 2.03 and 2.05 (6 H, 2 s); 2.09-2.25 (2 H, m); 2.25-2.45 (2 51% H, m); 2.59 (0.6 H, d, J = 6.9 Hz); 2.63 (0.4 H, d, J = 6.9 Hz); 3.33- 3.53 (4 H, m); 3.69-3.77 (1 H, m); 3.81-3.91 (1 H, m); 4.24-4.33 (1 H, m); 7.26-7.33 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 25.6; 30.0; 30.1; 30.7; 31.16; 31.2; 31.4; 31.5; 31.57; 31.6; 36.0; 37.6; 38.0; 38.1; 40.4; 40.5; 40.9; 42.3; 43.9; 45.2; 55.1; 56.5; 60.9; 67.81; 67.85; 76.0; 126.5; 126.7; 127.6; 127.7; 127.8; 137.4; 169.7; 169.7. 76 1 Ex. no. 71/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.24-1.36 (2 H, m); 1.56 (1 H, t, J = 7.3 Hz); 1.62 Acylation/ 335.3 (22%) (3 H, m); 1.83-2.11 (9 H, m); 2.15-2.31 (4 H, m); 2.33-2.44 (1 H, 29% [M + H]⁺ = 380.4 m); 2.59-2.68 (2 H, m); 2.69 (0.8 H, s); 2.71 (1.2 H, s); 3.34 (1.2 H, (100%), R_(t) = 2.7 s); 3.41 (0.8 H, s); 3.43-3.51 (2 H, m); 7.24-7.33 (3 H, m); 7.34- min. 7.42 (2 H, m). ¹³C-NMR (CDCl₃): 17.1; 30.0; 30.8; 31.2; 31.4; 32.5; 33.2; 33.3; 35.9; 37.5; 38.0; 38.1; 40.4; 41.5; 42.0; 42.5; 43.9; 45.2; 55.3, 56.2; 60.8; 124.5; 124.5; 126.5; 126.9; 127.6; 127.6; 127.7; 127.8; 137.5; 167.0; 167.1. 77 1 Ex. no. 71/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.96-1.02 (2 H, m); 1.25-1.37 (4 H, m); 1.57 (1 H, Acylation/ 321.3 (16%) t, J = 7.3 Hz); 1.62-1.70 (3 H, m); 1.83-1.99 (2 H, m); 2.03 (2.6 H, 25% [M + H]⁺ = 366.3 s); 2.04 (3.4 H, s); 2.16-2.25 (1 H, m); 2.29-2.38 (1 H, m); 2.45 (0.8 (100%), R_(t) = 2.6 H, s); 2.46 (1.2 H, s); 3.32 (1.2 H, s); 3.43 (0.8 H, s); 3.41-3.53 (2 H, min. s); 7.23-7.32 (3 H, m); 7.33-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 6.7; 6.7; 14.0; 30.1; 30.8; 31.1; 31.4; 35.8; 37.5; 38.0; 38.1; 39.3; 39.7; 40.4; 42.5; 44.2; 45.2; 55.4; 56.4; 60.8; 123.1; 123.2; 126.5; 126.8; 127.6; 127.6; 127.7, 127.8; 137.3; 167.2; 167.2. 78 1 Ex. no. 71/ [M + H]⁺ = 357.3, ¹H-NMR (CDCl₃): 1.26-1.36 (2 H, m); 1.55 (1 H, t, J = 7.3 Hz); 1.59- Acylation/ R_(t) = 2.4 min. 1.70 (3 H, m); 1.82-2.00 (2 H, m); 2.02 and 2.05 (6 H, 2 s); 2.13- 25% 2.40 (2 H, m); 2.67 (2 H, t, J = 7.3 Hz); 3.34 (1.1 H, s); 3.37 (0.9 H, s); 3.38-3.46 (3 H, m); 4.38-4.44 (2 H, m); 4.90 (2 H, dd, J = 7.8 and 6.3 Hz); 7.24-7.32 (3 H, m); 7.34-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 20.1; 30.1; 30.8; 31.1; 31.4; 31.5; 31.6; 35.8; 37.4; 37.9; 38.0; 38.1; 38.5; 39.8; 40.4; 42.3; 43.8; 44.9; 55.1; 56.3; 60.7; 77.4; 77.5; 126.5; 126.7; 127.5; 127.54; 127.6; 127.7; 137.3; 169.5; 169.6. 79 1 Ex. no. 71/ [M + H]⁺ = 357.4, ¹H-NMR (CDCl₃): 0.90 and 0.92 (6 H, 2 d, J = 6.3 Hz); 1.24-1.36 (2 Acylation/ R_(t) = 3.1 min. H, m); 1.50-1.70 (7 H, m); 1.77-1.99 (2 H, m); 2.02 and 2.04 (6 H, 2 58% s); 2.16-2.27 (3 H, m); 2.29-2.40 (1 H, m); 3.40 (1.2 H, s); 3.34 (0.8 H, s); 3.41-3.48 (2 H, m); 7.24-7.32 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 22.37; 22.4; 27.9; 28.0; 31.0; 30.9; 31.2; 31.5; 32.4; 32.9; 33.8; 36.0; 37.6; 38.0; 38.1; 40.3; 42.3; 43.9; 45.0; 55.2; 56.3; 60.8; 126.5; 126.7; 127.6; 127.63; 127.7; 127.8; 172.19; 172.2. 80 1 Ex. no. 71/ [M + H]⁺ = 354.4, ¹H-NMR (CDCl₃): 1.25-1.38 (2 H, m); 1.54-1.58 (1 H, m); 1.58 and Acylation/ R_(t) = 2.6 min. 1.60 (6 H, 2 s); 1.62-1.73 (3 H, m); 1.88-2.00 (2 H, m); 1.98 and 58% 2.02 (6 H, 2 s); 2.17-2.30 (2 H, m); 3.45 (0.7 H, s); 3.65 (1.3 H, s); 3.51 (1.3 H, t, J = 7.0 Hz); 3.79 (0.7 H, t, J = 7.0 Hz); 7.23-7.31 (3 H, m); 7.34-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 25.01; 25.07; 30.2; 30.5; 30.6; 31.4; 34.4; 36.6; 37.9; 38.0; 39.3; 43.2; 46.1, 46.3; 57.5; 57.9; 60.8; 121.6; 121.8; 126.5; 126.6; 127.4; 127.5; 127.7; 165.6; 165.9. 81 1 Ex. no. 71/ [M + H]⁺ = 371.4, ¹H-NMR (CDCl₃): 1.24-1.35 (2 H, m); 1.52-1.68 (6 H, m); 1.80-1.98 Acylation/ R_(t) = 2.6 min. (4 H, m); 2.02 and 2.04 (6 H, 2 s); 2.15-2.43 (2 H, m); 2.51-2.61 (1 40% H, m); 3.36-3.51 (6 H, m); 3.98-4.05 (2 H, m); 7.25-7.32 (3 H, m); 7.33-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 28.6; 30.1; 31.0; 31.1; 31.4; 35.7; 37.6; 38.0; 39.6; 39.8; 40.1; 42.3; 44.1; 44.6; 55.4; 55.9; 60.7; 67.3; 67.32; 126.5; 126.7; 127.5; 127.6; 127.8; 135.2; 137.4; 173.0; 173.1. 82 1 Ex. no. 71/ [M + H]⁺ = 373.3, ¹H-NMR (CDCl₃): 1.23 (2.4 H, s); 1.24 (3.6 H, s); 1.27-1.35 (2 H, m); Acylation/ R. = 2.5 min. 1.51-1.57 (1.2 H, m); 1.59-1.70 (2.8 H, m); 1.81-1.98 (4 H, m); 2.03 14% (2.4 H, s); 2.06 (3.6 H, s); 2.16-2.45 (4 H, m); 3.35 (1.2 H, s); 3.40 (0.8 H, s); 3.41-3.49 (2 H, m); 7.23-7.41 (5 H, m). The OH signal could not be identified. The ¹H-NMR spectrum in DMSO-d₆ shows the OH signal at 4.22 and 4.25 ppm. ¹³C-NMR (CDCl₃): 27.6; 29.1; 29.4; 29.5; 30.0; 30.7; 31.2; 31.3; 35.9; 37.2; 37.4; 37.9; 38.0; 40.3; 42.2; 44.2; 45.0; 55.3; 56.2; 60.7; 69.4; 74.7; 74.8; 75.2; 126.4; 126.9; 127.5; 127.7; 129.9, 137.4; 172.5; 172.6. 83 1 Ex. no. 71/ [M + H]⁺ = 387.4, ¹H-NMR (CDCl₃): 1.15 (2.6 H, s); 1.17 (3.4 H, s); 1.27-1.36 (2 H, m); Acylation/ R_(t) = 2.8 min. 1.51-1.57 (1.2 H, m); 1.59-1.70 (2.6 H, m); 1.80-1.99 (4 H, m); 77% 2.02 (2.8 H, s); 2.03 (3.4 H, m); 2.16-2.40 (4 H, m); 3.16 (1.3 H, s); 3.18 (1.7 H, s); 3.35 (1.2 H, s); 3.40 (0.8 H, s); 3.41-3.48 (2 H, m); 7.23-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 25.0; 25.0; 28.7; 29.1; 30.1; 30.7; 31.3; 31.5; 34.0; 34.0; 34.2; 35.9; 37.5; 38.0; 40.4; 42.3; 44.0; 44.9; 49.1; 55.3; 56.2; 60.7; 73.90; 73.94; 126.5; 126.7; 127.6; 127.7; 171.92; 171.94. 84 1 Ex. no. 71/ [M + H]⁺ = 357.3 ¹H-NMR (DMSO-d₆): 1.13-1.24 (2 H, m); 1.42-1.49 (2 H, m); 1.53- Acylation/ (29%) 1.63 (2 H, m); 1.68-1.78 (1 H, m); 1.90 (4 H, s); 1.92 (2 H, s); 1.82- 54% [MH − NHMe₂]⁺ = 1.91 (1 H, m, overlapped); 1.95-2.13 (6 H, m); 2.46-2.54 (2 H, m, 312.3 (100%), overlapped by the DMSO signal); 3.21 (0.8 H, s); 3.24 (1.2 H; t, J = R_(t) = 2.7 min. 7.1 Hz, overlapped by the water signal); 3.39 (1.2 H; s); 3.52 (0.8 H; t, J = 7.1 Hz); 5.70 (0.3 H, s); 5.77 (0.7 H, s); 7.23-7.26 (1 H, m); 7.31-7.39 (4 H, m). ¹³C-NMR (DMSO-d₆): 12.2; 29.9; 30.2; 30.9; 33.4; 33.6; 37.7; 41.7; 44.4; 59.8; 60.0; 75.2; 75.5; 126.2; 127.2; 127.4; 171.1; 171.3. 85 1 Ex. no. 71/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 0.10-0.19 (2 H, m); 0.51-0.58 (2 H, m); 1.08 (1 H, Acylation/ R_(t) = 2.8 min. m); 1.22-1.35 (2 H, m); 1.50-1.67 (4 H, m); 1.75-1.98 (2 H, m); 70% 2.02 (2.4 H, s); 2.03 (3.6 H, s); 3.31 (1.2 H, s); 2.17 (0.8 H, d, J = 6.7 Hz); 2.20 (1.2 H, d, J = 6.7 Hz); 2.18-2.40 (2 H, m); 3.38 (0.8 H, t, J = 7.2 Hz); 3.41 (0.8 H, s); 3.46 (1.2 H, t, J = 7.2 Hz); 7.22-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 4.3; 6.9; 30.1; 30.9; 31.2; 31.3; 35.9; 37.7; 37.9; 38.1; 39.5; 39.9; 40.2; 42.3; 43.9; 44.9; 55.0; 56.3; 60.8; 126.3; 126.7; 127.4; 127.5; 127.6; 135.6; 137.4; 171.38; 171.44. 86 1 Ex. no. 71/ [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.24-1.35 (2 H, m); 1.53 (1 H, m); 1.56-176 (5 H, Acylation/ R_(t) = 3.1 min. m); 1.78-1.98 (4 H, m); 2.02 (2.5 H, s); 2.04 (3.5 H, s); 2.10-2.24 (3 79% H, m); 2.30-2.42 (3 H, m); 2.74 (1 H, m); 3.33 (1.8 H, s); 3.37 (0.8 H, s); 3.38-3.46 (2 H, m); 7.22-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 18.6; 28.6; 30.0; 30.8; 31.2; 31.3; 32.2; 32.4; 35.8; 37.5; 38.0; 38.1; 40.2; 41.3; 41.6; 42.3; 43.6; 45.1; 53.4; 55.1; 56.3; 60.8; 126.3; 126.7; 127.6; 171.06; 171.09. 87 1 Ex. no. 83/ [M + H]⁺ = 373.4, ¹H-NMR (CDCl₃): 1.13 (6 H, s); 1.20-1.32 (2 H, m); 1.40-1.55 (6 H, Reduction/ R_(t) = 2.1 min. m); 1.60-1.70 (2 H, m); 1.75-1.92 (2 H, m); 2.02 (6 H, s); 2.27 (2 H, 55% br s); 2.34-2.40 (2 H, m); 2.48-2.54 (4 H, m); 3.17 (3 H, s); 7.24- 7.40 (5 H, m). ¹³C-NMR (CDCl₃): 23.2; 24.9; 31.0; 34.7; 37.6; 38.1; 38.2; 41.0; 49.1; 53.4; 53.9; 57.4; 60.4; 65.4; 74.3; 126.4; 127.4; 127.6. 88 3 Ex. no. 425/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.96 (3 H, dt, J = 7.4 and 2.8 Hz); 1.34-1.44 (2 H, Acylation/ 324.3, R_(t) = 3.0 m); 1.61-1.73 (6 H, m); 1.83-2.02 (4 H, m); 2.10 (3 H, s); 2.12 (3 H, 41% min. s); 2.21 (2 H, dt, J = 7.8 and 1.9 Hz); 3.29 (1 H, s); 3.36 (1 H, s); 3.46 (2 H, td, J = 14.6 and 7.2 Hz); 6.61 (1 H, t, J = 4.0 Hz); 6.84 (1 H, dd, J = 10.5 and 3.8 Hz). ¹³C-NMR (CDCl₃): 18.3; 18.4; 31.0; 31.2; 32.4; 33.0; 35.5; 36.3; 36.8; 37.2; 37.9; 38.1; 40.1; 42.0; 43.9; 45.0; 55.2; 55.5; 124.3; 124.5; 125.4; 125.6; 127.7; 127.9; 142.7. 89 3 Ex. no. 425/ [M − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.3 Hz); 1.28-135 (2 H, m); 1.37- Reductive 310.3, R_(t) = 2.0 1.41 (2 H, m); 1.43-1.47 (2 H, m); 1.51 (2 H, t, J = 6.9 Hz); 1.65- amination/ min. 1.71 (2H, m); 1.81-1.87 (2 H, m); 1.98-2.06 (2 H, m); 2.11 (6 H, s); 44% 2.34-2.38 (2 H, m); 2.39 (2 H, s); 2.50 (2 H, t, J = 6.8 Hz); 6.60 (1 H, dd, J = 3.8 and 0.9 Hz); 6.83 (1 H, dd, J = 3.8 and 0.9 Hz). ¹³C-NMR (CDCl₃): 14.1; 20.9; 31.0; 33.3; 33.8; 34.4; 38.1; 38.2; 40.8; 53.9; 56.8; 60.1; 124.3; 125.4, 126.1; 127.5. 90 1 Ex. no. 426/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.96 (3 H, dt, J = 7.4 and 2.6 Hz); 1.35-1.44 (2 H, Acylation/ 308.3, R_(t) = 2.9 m); 1.61-1.73 (6 H, m); 1.81-1.99 (4 H, m); 2.10 (3 H, s); 2.12 (3 H, 42% min. s); 2.19-2.23 (2 H, m); 3.28 (1 H, s); 3.36 (1 H, s); 3.46 (2 H, td, J = 14.6 and 7.2 Hz); 6.38 (1 H, ddd, J = 12.6, 4.0 and 1.7 Hz); 6.42 (1 H, ddd, J = 4.8, 4.0 and 3.2 Hz). ¹³C-NMR (CDCl₃): 14.0; 18.3; 18.4; 31.0; 31.2; 32.1; 32.8; 35.6; 36.3; 36.8; 37.2; 37.9; 38.05; 38.08; 40.1; 42.0; 43.9; 45.0; 55.2; 56.4; 60.0; 60.1; 106.0; 106.2; 160.3; 160.4; 121.0; 121.1; 121.3; 162.5; 165.4; 171.87; 171.91. 91 1 Ex. no. 426/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.3 Hz); 1.28-1.48 (6 H, m); 1.52 Reductive 294.3, R_(t) = 1.0 (2 H, t, J = 6.9 Hz); 1.64-1.70 (2 H, m); 1.83 (2 H, t, J = 11.4 Hz); amination/ min 1.93-2.04 (2 H, m); 2.11 (6 H, s); 2.34-2.38 (2 H, m); 2.40 (2 H, s); 49% 2.50 (2 H, t, J = 6.9 Hz,); 6.37 (1 H, dd, J = 4.0 and 1.7 Hz.); 6.42 (1 H, dd, J = 4.0 and 3.2 Hz). ¹³C-NMR (CDCl₃): 14.1; 20.9; 31.0; 33.1; 34.4; 38.0; 38.1; 40.8, 53.9; 56.8; 59.9; 65.6; 106.1 (d, J = 11 Hz); 121.1; 127.3; 129.2; 132.7; 133.1; 163.8 (d, J = 289 Hz). 94 3 Ex. no. 93/ [M + H]⁺ = 335.3, ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.3 Hz); 0.92-1.00 (2 H, m); 1.06- Reduction/ low UV activity 1.75 (25 H, m); 2.17 (6 H, s); 2.30-2.39 (4 H, m); 2.53 (2 H, t, J = 72% 6.8 Hz). ¹³C-NMR (CDCl₃): 14.1; 20.9; 26.2; 26.7; 29.4; 31.0; 33.1; 33.5; 36.1; 36.3; 37.3; 37.8; 41.0; 54.4; 56.8; 56.9; 68.3. 96 3 Ex. no. 95/ [M + H]⁺ = 321.3, ¹H-NMR (CDCl₃): 0.89 (3 H , t, J = 7.3 Hz); 1.00-1.10 (2 H, m); 1.22- Reduction/ low UV activity 1.84 (23 H, m); 2.18 (6 H, s); 2.30-2.40 (4 H, m); 2.55 (2 H, t, J = 66% 6.7 Hz). ¹³C-NMR (CDCl₃): 14.1; 20.9; 25.0; 29.5; 30.8; 33.3; 35.1; 36.0; 36.3; 36.7; 37.1; 37.3; 41.0; 54.2; 56.6; 56.7; 68.1. 97 3 Ex. no. 424/ [M + H]⁺ = 321.4, ¹H-NMR (CDCl₃): 0.948 and 0.953 (3 H, 2 t, J = 7.4); 1.16-1.39 (6 Acylation/ R_(t) = 2.8 min. H, m); 1.40-1.84 (14 H, m); 2.00-2.12 (1 H, m); 2.16-2.23 (2 H, m); 89% 2.25 (2.4 H, s); 2.28 (3.6 H, s); 3.15 (1.2 H, s); 3.22 (0.8 H, s); 3.46 (0.8 H, t, J = 7.1 Hz); 3.50 (1.2 H, t, J = 7.2 Hz). 98 3 Ex. no. 97/ [M + H]⁺ = 307.4, ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.3 Hz); 1.20-1.36 (8 H, m); 1.38- Reduction/ R_(t) = 1.3 min. 1.70 (14 H, m); 2.04 (1 H, tt, J = 10.9 and 7.6 Hz); 2.26 (6 H, s); 84% 2.30-2.40 (4 H, m); 2.57 (2 H, t, J = 6.5 Hz). ¹³C-NMR (CDCl₃): 14.1; 20.7; 25.0; 27.2; 28.4; 30.7; 33.1; 34.9; 38.0; 41.5; 44.5; 54.6; 56.9; 57.6; 69.2. 99 3 Ex. no. 424/ [M + H]⁺ = 333.4, ¹H-NMR (CDCl₃): 1.12-1.38 (6 H, m); 1.40-2.18 (17 H, m); 2.25 (2 Acylation/ R_(t) = 2.9 min. H, s); 2.28 (4 H, s); 2.28-2.37 (2 H, m); 3.05 (1.3 H, s); 3.15 (1 H, 86% m); 3.21 (0.7 H, s); 3.37 (0.7 H, t, J = 7.1 Hz); 3.49 (1.3 H, t, J = 7.1 Hz). ¹³C-NMR (CDCl₃): 18.0; 18.1; 24.7; 25.0; 25.1; 26.9; 27.1; 28.48; 28.53; 29.8; 29.9; 31.7; 33.4; 37.7; 37.9; 38.0; 38.4; 40.5; 42.5; 44.0; 44.1; 44.5; 44.7; 57.8; 57.8; 58.8; 59.4; 173.1; 173.3. 100 3 Ex. no. 424/ [M + H]⁺ = 319.4, ¹H-NMR (CDCl₃): 0.68-0.75 (2 H, m); 0.94-1.66 (2 H, m); 1.14-1.40 Acylation/ R_(t) = 2.7 min. (6 H, m); 1.41-1.78 (12 H, m); 1.84 (1 H, t, J = 7.1 Hz); 2.07 (1 H, 75% m); 2.26 (3.6 H, s), 2.28 (2.4 H, s); 3.23 (0.8 H, s); 3.35 (1.2 H, s); 3.51 (1.2 H, t, J = 7.1 Hz); 3.66 (0.8 H, t, J = 7.1 Hz). ¹³C-NMR (CDCl₃): 7.2; 12.0; 12.3; 25.0; 25.2; 27.05; 27.1; 27.6; 28.51; 28.54; 29.7; 29.8; 32.1; 33.4; 37.7; 37.9; 37.8; 40.8; 42.4; 44.2; 44.3; 44.8; 45.3; 57.7; 57.9; 59.2; 60.3; 172.0; 172.1. 101 3 Ex. no. 100/ [M + H]⁺ = 305.4, ¹H-NMR (CDCl₃): 0.07-0.13 (2 H, m); 0.44-0.50 (2 H, m); 0.90 (1 H, Reduction/ R_(t) = 0.6 min. m); 1.20-1.35 (6 H, m), 1.38-1.74 (12 H, m); 2.04 (1 H, tt, J = 10.8 84% and 7.6 Hz); 2.26 (6 H, s); 2.28 (2 H, d, J = 6.6 Hz); 2.42 (2 H, s); 2.63 (2 H, t, J = 6.8 Hz). ¹³C-NMR (CDCl₃): 3.8; 9.7; 25.0; 27.2; 28.4; 33.0; 34.9; 37.9; 41.5; 44.3; 54.6; 57.7; 61.8; 69.4. 102 3 Ex. no. 99/ [M + H]⁺ = 319.4, ¹H-NMR (CDCl₃): 1.18-1.34 (6 H, m); 1.40-1.92 (16 H, m); 1.98- Reduction/ R_(t) = 1.4 min. 2.10 (3 H, m); 2.26 (6 H, s); 2.31 (2 H, s); 2.44 (2 H, d, J = 6.9 Hz); 89% 2.48-2.60 (3 H, m). ¹³C-NMR (CDCl₃): 18.6; 25.0; 27.2; 27.7; 28.4; 33.1; 34.9; 35.4; 37.9; 41.6; 44.3; 54.8; 57.6; 63.3; 69.3. 103 3 Ex. no. 424/ [M + H]⁺ = 333.4, ¹H-NMR (CDCl₃): 0.11-0.16 (2 H, m); 0.46-0.60 (2 H, m); 1.08 (1 H, Acylation/ R_(t) = 2.8 min. m); 1.12-1.84 (18 H, m); 2.05 (1 H, tt, J = 11.0 and 7.6 Hz); 2.17 (2 68% H, dd, J = 6.7 and 4.8 Hz); 2.24 (2.5 H, s); 2.25 (3.5 H, s); 3.13 (1.2 H, s); 3.23 (0.8 H, s); 3.42 (0.8 H, t, J = 7.1 Hz); 3.51 (1.2 H, t, J = 7.2 Hz). ¹³C-NMR (CDCl₃): 4.4; 6.9; 7.0; 25.10; 25.12; 26.9; 27.1; 28.46; 28.50; 29.8; 29.79; 29.83; 31.9; 33.6; 37.81; 37.83; 39.3; 39.7; 40.4; 42.6; 44.0; 44.1; 44.3; 45.4; 53.4; 57.76; 57.85; 58.8; 60.3; 171.1; 171.2. 104 3 Ex. no. 103/ [M + H]⁺ = 319.4, ¹H-NMR (CDCl₃): 0.00-0.05 (2 H, m); 0.32-0.44 (2 H, m); 0.64 (1 H, Reduction/ R_(t) = 1.8 min. m); 1.20-1.70 (20 H, m); 2.04 (1 H, tt, J = 10.7 and 7.6 Hz); 2.26 (6 58% H, s); 2.31 (2 H, s); 2.42-2.48 (2 H, m); 2.54 (2 H, t, J = 6.8 Hz). ¹³C-NMR (CDCl₃): 4.3; 9.2; 25.0; 27.2; 28.4; 33.2; 34.0; 35.1; 37.9; 41.3; 44.3; 54.6; 57.0; 57.7; 69.5. 105 3 Ex. no. 424/ [M + H]⁺ = 347.4, ¹H-NMR (CDCl₃): 1.13-1.95 (20 H, m); 2.00-2.19 (3 H, m); 2.25 (2.7 Acylation/ R_(t) = 3.1 min. H, s); 2.27 (3.3 H, s); 2.34 (1.2 H, d, J = 7.4 Hz); 2.35 (0.8 H, d, J = 54% 7.4 Hz); 2.73 (1 H, m); 3.16 (1.2 H, s); 3.20 (0.8 H, s), 3.46 (0.8 H, t, J = 7.1 Hz); 3.48 (1.2 H, t, J = 7.2 Hz). ¹³C-NMR (CDCl₃): 18.6; 18.8; 25.11; 2515; 26.9; 27.1; 28.48; 28.54; 28.6; 29.7; 32.1; 32.37; 32.39; 33.6; 37.7; 37.9; 40.6; 41.1; 41.5; 42.4; 44.0; 44.1; 44.3; 45.6; 57.7; 57.8; 58.5; 60.3; 170.8; 171.0. 108 1 Ex. no. 427/ [M + H]⁺ = 347.4, ¹H-NMR (CDCl₃): 0.97 and 0.975 (2 t, 3H, J = 7.4 Hz); 1.30-1.42 (m, Acylation/ R_(t) = 2.8 min. 2H); 1.58 (t, 1H, J = 7.2 Hz); 1.61-2.00 (m, 11H); 2.18-2.25 (m, 2H); 68% 3.05 and 3.06 (2 t, 4H, J = 7.0 Hz); 3.30 and 3.36 (2 s, 2H); 3.40- 3.49 (m, 2H); 6.87 and 6.89 (2 t, 1H, J = 3.6 Hz); 7.07 and 7.11 (2 dd, 1H, J = 5.1, 1.5 Hz); 7.26 and 7.29 (2 dd, 1H, J = 5.1, 1.5 Hz). ¹³C-NMR (CDCl₃): 13.7; 14.0; 15.9; 16.1; 18.3; 18.4; 18.9; 30.8; 31.0; 31.04; 31.7; 36.4; 36.9; 37.8; 40.2; 42.2; 43.9; 45.0; 46.7; 46.8; 55.6; 56.7; 58.7; 59.0; 123.5; 123.7; 124.6; 125.0; 126.4; 126.6; 171.8; 171.9. 109 2 Ex. no. 428/ [M + H]⁺ = 347.2, ¹H-NMR (CDCl₃): 0.87-0.99 (m, 3H); 1.33-1.42 (m, 2H); 1.57-1.87 Acylation/ R_(t) = 1.8 min. (m, 12H); 2.14 (t, 1H, J = 7.6 Hz); 2.20 (t, 1H, J = 7.5 Hz); 3.07 (t, 70% 4H, J = 6.8 Hz); 3.11 (s, 1H); 3.20 (s, 1H); 3.44-3.58 (m, 2H); 6.84 (d, 0.5H, J = 3.5 Hz); 6.87 (d, 0.5H, J = 3.5 Hz); 7.05-7.11 (m, 1H); 7.24-7.30 (m, 1H). ¹³C-NMR (CDCl₃): 13.96; 14.0; 15.9; 16.4; 30.76; 30.81; 36.3; 36.7; 40.1; 42.2; 44.0; 45.1; 46.71; 46.72; 123.6; 124.7; 126.4, 126.5; 171.8. 110 1 Ex. no. 429/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 0.92-1.00 (m, 3H); 1.21-1.32 (m, 2H); 1.50 (t, 1H, Acylation/ R_(t) = 2.8 min. J = 7.2 Hz); 1.58-1.82 (m, 9H); 1.94-2.14 (m, 2H); 2.17-2.26 (m, 73% 2H); 2.92-2.98 (m, 4H); 3.25 (s, 1H); 3.38-3.48 (m, 3H); 7.26-7.34 (m, 3H); 7.36-7.46 (m, 2H). ¹³C-NMR (CDCl₃): 13.7; 14.01; 14.04; 16.5; 16.8; 18.3; 18.5; 18.9; 28.5; 29.4; 30.9; 31.2; 36.3; 36.9; 37.7; 40.4; 42.4; 43.8; 45.0; 46.6; 46.7; 55.3; 56.6, 59.3; 59.6; 126.5; 126.7; 127.5; 127.7; 127.87; 127.94; 171.8, 171.9. 194 2 Ex. no. 430/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 0.89 and 0.94 (2 t, 3H, J = 7.4 Hz); 1.25-1.35 (m, Acylation/ R_(t) = 2.7 min. 2H); 1.54-2.00 (m, 12H); 2.10 and 2.19 (2 t, 2H, J = 7.5 Hz); 2.96 (t, 60% 4H, J = 6.9 Hz); 3.14 and 3.05 (2s, 2H); 3.49 (td, 2H, J = 14.0, 7.1 Hz); 7.25-7.34 (m, 3H); 7.38-7.45 (m, 2H). ¹³C-NMR (CDCl₃): 13.9; 14.0; 16.6; 18.4; 28.8; 28.9; 30.88; 30.9, 34.4; 36.3; 36.7; 40.4; 42.4; 44.1; 45.2; 46.6; 56.1; 57.7; 59.3; 126.6; 126.7; 127.5; 127.6; 127.8; 127.9; 137.6; 171.8. 112 1 Ex. no. 429/ [M + H]⁺ = 327.4, ¹H-NMR (CDCl₃): 0.95 (t, 3H, J = 7.3 Hz); 1.28-1.43 (m, 4H); 1.55- Reductive R_(t) = 0.7 min. 1.68 (m, 4H); 1.72-1.88 (m, 6H); 2.05 (br s, 2H); 2.66-2.73 (m, 2H); amination/ 2.80 (s, 2H); 2.83-2.90 (m, 2H); 3.10 (t, 4H, J = 7.0 Hz); 7.31-7.38 52% (m, 3H); 7.42-7.49 (m, 2H). ¹³C-NMR (CDCl₃): 13.8; 16.4; 20.4; 29.0; 29.2; 33.2; 41.5; 46.9; 56.4; 64.5; 127.4; 127.7; 128.3. 113 2 Ex. no. 430/ [M + H]⁺ = 327.4, ¹H-NMR (CDCl₃): 0.78-0.94 (m, 3H); 1.20-1.50 (m, 6H); 1.54-1.80 Reductive R_(t) = 1.9 min. (m, 8H); 1.90-2.10 (m, 2H); 2.17 (s, 2H); 2.28-2.43 (m, 2H); 2.46- amination/ 2.58 (m, 2H); 2.93-3.00 (m, 4H); 7.25-7.34 (m, 3H); 7.40 (t, 2H, J = 42% 7.6 Hz). ¹³C-NMR (CDCl₃): 14.0; 16.7; 20.8; 26.9; 27.0; 29.1; 30.9; 34.2; 41.3; 46.7; 54.4; 56.7; 126.5; 127.8; 127.9. 114 3 Ex. no. 17/ [M + H]⁺ = 293.3, ¹H-NMR (CDCl₃): 1.20-1.28 (m, 2H); 1.68 (dt, 2H, J = 3.0 and 14.0 Alkylation/ R_(t) = 2.2 min. Hz); 1.89 (t, 2H, J = 7.0 Hz); 2.11 (s, 6H); 2.20 (dt, 2H, J = 3.1 and 56% 13.0 Hz); 2.45 (br d, 2H, J = 13.8 Hz,); 2.85 (s, 3H); 3.23-3.28 (m, 2H); 6.85 (br d, 1H, J = 3.4 Hz); 7.02 (dd, 1H, J = 3.6 and 5.1 Hz); 7.20 (dd, 1H, J = 1.0 and 5.1 Hz). ¹³C-NMR (CDCl₃): 28.3 (2C); 29.8 (2C); 30.3; 31.7; 38.0 (2C); 44.3; 46.1; 58.4; 122.7; 123.6; 125.9; 145.8; 178.9. 115 3 Ex. no. 17/ [M + H]⁺ = 335.3, ¹H-NMR (CDCl₃): 0.92 (dt, 3H, J = 7.4 Hz); 1.20-1.35 (m, 4H); 1.44- Alkylation/ R_(t) = 2.8 min. 1.53 (m, 2H); 1.61-1.73 (m, 2H); 1.87 (t, 2H, J = 6.9 Hz); 2.10 (m, 67% 6H); 2.20 (dt, 2H, J = 13.1 Hz); 2.44 (d, 2H, J = 2.6 and 13.6 Hz); 3.21-3.30 (m, 4H); 6.83-6.86 (m, 1H); 6.99-7.03 (m, 1H); 7.18-7.21 (m, 1H). ¹³C-NMR (CDCl₃): 13.7; 19.9; 28.2 (2C); 29.3; 30.4; 31.8 (2C); 37.9 (2C); 42.2; 43.7; 44.6; 58.4; 122.7; 123.6; 125.9; 145.9; 178.7. 116 3 Ex. no. 17/ [M + H]⁺ = 361.3, ¹H-NMR (CDCl₃): 1.16 (m, 4H); 1.47-1.58 (m, 2H); 1.60-1.74 (m, Alkylation/ R_(t) = 3.0 min, 6H); 1.87 (t, 2H, J = 6.9 Hz); 2.11 (s, 6H); 2.12-2.25 (m, 3H); 2.45 18% (d, 2H, J = 13.8 Hz); 3.21 (d, 2 H, J = 7.8 Hz); 3.25-3.30 (m, 2H); 6.86 (d, 1H, J = 3.5 Hz); 7.02 (dd, 1H, J = 3.6 and 5.1 Hz); 7.20 (dd, 1H, J = 1.1 and 5.1 Hz). ¹³C-NMR (CDCl₃): 25.1 (2C); 28.2; 30.3 (2C); 30.6; 31.8; 37.9 (2C); 38.0; 44.1; 44.6; 47.5; 58.5; 122.8; 123.6; 126.0; 178.8. 118 2 Ex. no. 2/ [M + H]⁺ = 301.3, ¹H-NMR (DMSO-d₆): 0.93 (d, 2H, J = 13.0 Hz); 1.04 (dt, 2H, J = Alkylation/ R_(t) = 2.4 min. 14.0, 3.3 Hz); 1.45 (t, 2H, J = 6.9 Hz); 1.71 (dd, 2H, J = 14.8, 2.6 71% Hz); 1.82 (dt, 2H, J = 13.6, 3.0 Hz); 2.25 (s, 6H); 2.58 (s, 2H); 2.65 (s, 3H); 3.06-3.11 (m, 2H); 7.12-7.20 (m, 3H); 7.23-7.29 (m, 2H). ¹³C-NMR (DMSO-d₆): 26.7; 27.9; 28.8; 29.1; 36.2; 36.8; 43.5; 45.1; 56.6; 125.5; 127.6; 130.5, 139.0; 177.7. 119 1 Ex. no. 1/ [M + H]⁺ = 301.3, ¹H-NMR (CDCl₃): 1.52-1.60 (m, 4H); 1.67-1.75 (m, 2H); 1.83-1.94 Alkylation/ R_(t) = 2.1 min. (m, 4H); 2.28 (s, 6H); 2.78 (s, 3H); 2.79 (s, 2H); 3.21-3.42 (m, 2H); 45% 7.14-7.20 (m, 1H); 7.21-7.25 (m, 4H). ¹³C-NMR (CDCl₃): 28.4; 29.4; 29.6; 32.8; 36.8; 37.4; 42.6; 46.0; 57.6; 125.7; 127.7; 130.7; 139.2; 179.0. 120 2 Ex. no. 2/ [M + H]⁺ = 343.3, ¹H-NMR (CDCl₃): 0.90 (t, 3H, J = 7.3 Hz); 1.02 (d, 2H, J = 13.3 Hz); Alkylation/ R_(t) = 3.0 min 1.13 (dt, 2H, J = 14.0, 3.3 Hz); 1.26 (qd, 2H, J = 14.0, 7.3 Hz); 1.39- 34% 1.48 (m, 2H); 1.58 (t, 2H, J = 7.0 Hz); 1.71-1.78 (m, 2H); 2.10 (dt, 2H, J = 13.4, 2.9 Hz); 2.30 (s, 6H); 2.61 (s, 2H); 3.11 (t, 2H, J = 6.9 Hz); 3.22 (t, 2H, J = 7.2 Hz); 7.09-7.13 (m, 2H); 7.15-7.28 (m, 3H). ¹³C-NMR (CDCl₃): 13.7; 19.9; 27.2; 28.6; 29.3; 29.6; 36.9; 37.0; 42.1; 43.6; 44.8; 57.2; 125.6; 127.6; 127.7; 130.7; 139.5; 179.0. 121 1 Ex. no. 1/ [M + H]⁺ = 343.3, ¹H-NMR (CDCl₃): 0.91 (t, 3H, J = 7.3 Hz); 1.23-1.34 (m, 2H); 1.41- Alkylation/ R_(t) = 2.8 min. 1.61 (m, 6H); 1.69-1.77 (m, 2H); 1.82-1.92 (m, 4H); 2.28 (s, 6H); 35% 2.81 (s, 2H); 3.19-3.25 (m, 4H); 7.13-7.19 (m, 1H); 7.20-7.25 (m, 4H). ¹³C-NMR (CDCl₃): 13.8; 20.0; 28.5; 29.3; 29.4; 32.7; 36.9; 37.5; 42.1; 43.1; 43.6; 57.6; 125.7; 127.8; 130.8; 139.4; 178.8. 222 2 Ex. no. 2/ [M + H]⁺ = 369.3, ¹H-NMR (CDCl₃): 1.00-1.20 (m, 6H); 1.45-1.65 (m, 8H); 1.70-1.78 Alkylation/ R_(t) = 3.2 min. (m, 2H); 2.00-2.20 (m, 3H); 2.31 (s, 6H); 2.62 (s, 2H); 3.11-3.18 (m, 31% 4H); 7.09-7.28 (m, 5H). ¹³C-NMR (CDCl₃): 25.1; 27.1; 28.6; 29.7; 30.2; 36.9; 37.0; 44.1; 44.7; 47.5; 57.3; 125.6; 127.7; 130.7; 139.4; 179.2. 123 1 Ex. no. 1/ [M + H]⁺ = 369.4, ¹H-NMR (CDCl₃): 1.16-1.26 (m, 2H); 1.48-1.80 (m, 13H); 1.84-1.94 Alkylation/ R_(t) = 3.0 min. (m, 3H); 2.09-2.18 (m, 1H); 2.29 (s, 6H); 2.83 (s, 2H); 3.17 (d, 2H, 16% J = 7.8 Hz); 3.26 (t, 2H, J = 6.9 Hz); 7.15-7.29 (m, 5H). ¹³C-NMR (CDCl₃): 25.1; 28.6; 29.4; 30.3; 32.7; 37.0; 37.6; 38.0; 43.2; 44.0; 47.4; 57.7; 125.7; 127.8; 130.8; 139.4; 179.0. 124 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.43-1.51 (m, 2H); 1.73-1.82 (m, 2H); 1.96-2.09 Alkylation/ 248.3 (100%) (m, 4H); 2.10 (s, 6H); 2.18 (s, 2H); 2.83 (s, 3H); 3.21 (s, 2H); 6.85 38% [M + H]⁺ = 293.3 (dd, 1H, J = 1.1, 3.6 Hz); 7.04 (dd, 1H, J = 3.6, 5.1 Hz); 7.24 (dd, (70%), R_(t) = 1.4 1H, J = 1.1, 5.1 Hz). min. ¹³C-NMR (CDCl₃): 29.7; 32.7; 32.9; 35.3; 38.0; 44.0; 59.3; 62.4; 123.4; 124.9; 126.3; 173.8. 125 1 Ex. no. 24a/ [M + H]⁺ = 335.3, ¹H-NMR (CDCl₃): 0.93 (t, 3H, J = 7.3 Hz); 1.26-1.36 (m, 2H); 1.42- Alkylation/ R_(t) = 2.1 min. 1.52 (m, 4H); 1.72-1.81 (m, 2H); 1.95-2.09 (m, 4H); 2.10 (s, 6H); 52% 2.18 (s, 2H); 3.20 (s, 2H); 3.25 (t, 2H, J = 7.3 Hz); 6.85 (dd, 1H, J = 1.1, 3.6 Hz); 7.04 (dd, 1H, J = 3.6, 5.1 Hz); 7.24 (dd, 1H, J = 1.1, 5.1 Hz). ¹³C-NMR (CDCl₃): 13.8; 20.0; 29.3; 32.7; 32.8; 35.5; 38.1; 42.1; 44.3; 57.9; 59.3; 123.4; 124.9; 126.3; 142.5; 173.5. 126 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.16-1.26 (m, 2H); 1.42-1.59 (m, 4H); 1.60-1.82 Alkylation/ 316.3 (100%) (m, 7H); 1.97-2.17 (m, 4H); 2.12 (s, 6H); 2.19 (s, 2H); 3.19 (d, 2H, 33% [M + H]⁺ = 361.4 J = 7.9 Hz); 3.24 (s, 2H); 6.87 (br s, 1H); 7.03-7.07 (m, 1H); 7.23- (70%), R_(t) = 2.7 7.28 (m, 1H). min. ¹H-NMR (DMSO-d₆): 1.09-1.19 (m, 2H); 1.30-138 (m, 2H); 1.44- 1.74 (m, 9H); 1.77-1.94 (m, 2H); 2.01 (s, 6H); 2.08 (s, 2H); 2.09- 2.18 (m, 2H); 3.07 (d, 2H, J = 7.8 Hz); 3.16 (s, 2H); 6.94 (s, 1H); 7.04-7.08 (m, 1H); 7.40-7.45 (m, 1H). ¹³C-NMR (DMSO-d₆): 24.6; 29.7; 32.0; 35.1; 37.3; 37.6; 38.9; 43.0; 46.3; 57.8; 58.7; 123.5; 124.7; 126.3; 143.3; 172.4. 127 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.12-1.22 (m, 2H); 1.42-1.56 (m, 4H); 1.57-1.70 Alkylation/ 316.3 (100%) (m, 4H); 1.73-1.81 (m, 2H); 2.01-2.17 (m, 5H); 2.18 (s, 6H); 2.36 (s, 25% [M + H]⁺ = 361.4 2H); 3.06 (s, 2H); 3.15 (d, 2H, J = 7.8 Hz); 6.91 (br d, 1H, J = 3.4 (8%), R_(t) = 3.1 Hz); 7.07 (dd, 1H, J = 3.6, 5.1 Hz); 7.29 (br d, 1H, 5.0 Hz). min. ¹³C-NMR (CDCl₃): 25.1; 30.4; 32.4; 32.8; 35.6; 38.0; 38.1; 43.4; 47.4; 59.0; 124.2; 125.8; 126.5; 173.6. 128 1 Ex. no. 24a/ [M + H]⁺ = 361.4, ¹H-NMR (CDCl₃): 1.41-1.50 (2 H, m); 1.55-1.70 (5 H, m); 1.72-1.91 Alkylation/ R_(t) = 2.7 min. (4 H, m); 1.93-2.04 (5 H, m); 2.10 (6 H, s); 2.17 (2 H, s); 2.25 (1 H, 61% td, J = 15.6 and 7.9 Hz); 3.14-3.20 (4 H, m); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 18.6; 28.2; 32.7; 32.8; 33.7; 34.3; 35.5; 38.1; 40.5; 44.3; 58.2; 59.3; 123.4; 124.9; 126.3; 173.4. 129 2 Ex. no. 24b/ [M + H]⁺ = 361.3, ¹H-NMR (CDCl₃): 1.42-1.65 (6 H, m); 1.70-1.91 (4 H, m); 1.93-2.09 Alkylation/ R_(t) = 3.1 min. (6 H, m); 2.10 (6 H, s); 2.22 (1 H, td, J = 15.6 and 7.9 Hz); 2.31 (2 H, 50% s); 3.03 (2 H, s); 3.13 (2 H, t, J = 7.4 Hz); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 18.5; 28.2; 32.7; 32.9; 33.6; 34.2; 35.5; 38.1; 40.5; 43.8; 58.7; 59.5; 123.4; 125.0; 126.2; 173.4. 130 1 Ex. no. 24a/ [M + H]⁺ = 347.3, ¹H-NMR (CDCl₃): 0.03-0.09 (2 H, m); 0.44-0.49 (2 H, m); 0.60-0.70 Alkylation/ R_(t) = 2.5 min. (1 H, m); 1.38-1.50 (4 H, m); 1.72-1.80 (2 H, m); 1.90-2.09 (4 H, 58% m); 2.10 (6 H, s); 2.18 (2 H, s); 3.23 (2 H, s); 3.34 (2 H, t, J = 7.3 Hz); 6.85 (1 H, d, J = 3.4 Hz); 7.04 (1 H, dd, J = 5.0 and 3.5 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 4.3; 8.6; 32.5; 32.7; 32.8; 35.5; 38.0; 42.6; 44.3; 58.5; 59.3; 123.4; 124.8; 126.3; 173.5. 131 2 Ex. no. 24b/ [M + H]⁺ = 347.3, ¹H-NMR (CDCl₃): 0.02 (2 H, q, J = 5.4 Hz); 0.39-0.45 (2 H, m); Alkylation/ R_(t) = 2.9 min. 0.55-0.65 (1 H, m); 1.36 (2 H, dd, J = 14.4 and 7.0 Hz); 1.42-1.51 38% (2 H, m); 1.70-1.79 (2 H, m); 1.92-2.09 (4 H, m); 2.10 (6 H, s); 2.32 (2 H, s); 3.08 (2 H, s); 3.30 (2 H, t, J = 7.3 Hz); 6.85 (1 H, d, J = 3.5 Hz); 7.04 (1 H, dd, J = 5.1 and 3.8 Hz); 7.24 (1 H, d, J = 5.1 Hz). ¹³C-NMR (CDCl₃): 4.3; 8.6; 32.4; 32.7; 32.9; 35.5; 38.1; 42.6; 43.9; 59.0; 59.5; 123.4; 124.9; 126.2; 173.5. 132 1 Ex. no. 24a/ [M + H]⁺ = 347.3, ¹H-NMR (CDCl₃): 1.40-1.49 (2 H, m); 1.63-1.78 (4 H, m); 1.85-2.09 Alkylation/ R_(t) = 2.5 min. (8 H, m); 2.10 (6 H, s); 2.17 (2 H, s); 2.52 (1 H, td, J = 15.6 and 7.8 69% Hz); 3.17 (2 H, s); 3.29 (2 H, d, J = 7.6 Hz); 6.84 (1 H, d, J = 3.4 Hz); 7.04 (1 H, dd, J = 5.0 and 3.6 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 18.4; 26.4; 32.6; 32.8; 33.9; 35.7; 38.1; 44.1; 47.8; 58.2; 59.3; 123.4; 124.9; 126.3; 173.6. 133 2 Ex. no. 24b/ [M + H]⁺ = 347.3 ¹H-NMR (CDCl₃): 1.40-1.48 (2 H, m); 1.63-1.77 (4 H, m); 1.80-2.09 Alkylation/ R_(t) = 2.9 min. (8 H, m); 2.10 (6 H, s); 2.31 (2 H, s); 2.47 (1 H, sept, J = 7.7 Hz); 83% 3.01 (2 H, s); 3.25 (2 H, d, J = 7.6 Hz); 6.85 (1 H, d, J = 3.5 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, d, J = 5.1 Hz). ¹³C-NMR (CDCl₃): 18.4; 26.4; 32.7; 32.8; 33.9; 35.7; 38.1, 43.6; 47.8; 58.9; 59.6; 123.4; 125.0; 126.2; 173.6. 134 1 Ex. no. 24a/ [M + H]⁺ = 333.3 ¹H-NMR (CDCl₃): 0.18-0.23 (2 H, m); 0.49-0.55 (2 H, m); 0.83-0.94 Alkylation/ R_(t) = 2.2 min. (1 H, m); 1.44-1.52 (2 H, m); 1.74-1.83 (2 H, m); 1.90-2.08 (4 H, 61% m); 2.11 (6 H, s); 2.19 (2 H, s); 3.13 (2 H, d, J = 7.1 Hz); 3.32 (2 H, s); 6.85 (1 H, d, J = 3.5 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, d, J = 4.4 Hz). ¹³C-NMR (CDCl₃): 3.4; 9.1; 19.8; 32.7; 32.9; 35.6; 38.1; 44.2; 47.0; 58.2; 59.3; 123.4; 124.9; 126.3; 173.4. 135 2 Ex. no. 24b/ [M + H]⁺ = 333.3, ¹H-NMR (CDCl₃): 0.14-0.19 (2 H, m); 0.44-0.50 (2 H, m); 0.78-0.88 Alkylation/ R_(t) = 2.7 min. (1 H, m); 1.44-1.53 (2 H, m); 1.72-1.81 (2 H, m); 1.93-2.09 (4 H, 40% m); 2.10 (6 H, s); 2.33 (2 H, s); 3.10 (2 H, d, J = 7.1 Hz); 3.16 (2 H, s); 6.86 (1 H, dd, J = 3.5 and 1.0 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 3.4; 9.1; 32.7; 32.9; 35.7; 38.1; 43.7; 47.0; 58.7; 59.6; 123.4; 125.0; 126.2; 173.4. 136 1 Ex. no. 24a/ [M + H]⁺ = 377.3, ¹H-NMR (CDCl₃): 1.40-1.52 (3 H, m); 1.63-1.93 (6 H, m); 1.95-2.08 Alkylation/ R_(t) = 2.3 min. (5 H, m); 2.10 (6 H, s); 2.17 (2 H, s); 3.20-3.27 (2 H, m); 3.28-3.41 57% (2 H, m); 3.67-3.74 (1 H, m); 3.75-3.88 (2 H, m); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.1 Hz); 7.23 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 25.6; 31.4; 32.67; 32.72; 32.74; 33.3; 35.6; 38.0; 40.0; 44.2; 58.4; 59.2; 67.7; 77.0, 123.4; 124.8; 126.2; 173.6. 137 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.39-1.50 (3 H, m); 1.60-1.80 (4 H, m); 1.80-1.90 Alkylation/ 332.3 (100%) (2 H, m); 1.94-2.09 (5 H, m); 2.10 (6 H, s); 2.31 (2 H, s); 3.05-3.12 53% [M + H]⁺ = 377.4 (2 H, m); 3.24-3.38 (2 H, m); 3.64-3.71 (1 H, m); 3.72-3.85 (2 H, (10%), R_(t) = 2.6 m); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.1 min. Hz); 7.23 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 25.6; 31.4; 32.7; 32.73; 32.8; 33.2; 35.6; 39.9; 43.6; 58.9; 59.5; 67.7; 76.9; 123.4; 124.9; 126.2; 173.6. 138 1 Ex. no. 24a/ [M + H]⁺ = 377.4, ¹H-NMR (CDCl₃): 1.28-1.40 (2 H, m); 1.43-1.53 (4 H, m); 1.62-1.90 Alkylation/ R_(t) = 2.2 min. (3 H, m); 1.95-2.09 (4 H, m); 2.10 (6 H, s); 2.20 (2 H, s); 3.14 (2 H, 51% d, J = 7.3 Hz); 3.23 (2 H, s); 3.35 (2 H, dt, J = 11.8 and 1.9 Hz); 3.96 (2 H, br dd, J = 11.5 and 2.6 Hz); 6.85 (1 H, dd, J = 3.3 and 1.1 Hz); 7.04 (1 H, dd, J = 4.9 and 3.6 Hz); 7.24 (1 H, d, J = 4.9 Hz). ¹³C-NMR (CDCl₃): 30.7; 32.7; 32.8; 33.7; 35.8; 38.0; 44.1; 48.4; 59.2; 59.9; 67.5; 67.7; 123.5; 124.8; 126.3; 174.1. 139 2 Ex. no. 24b/ [M + H]⁺ = 377.4, ¹H-NMR (CDCl₃): 1.31 (2 H, ddd, J = 17.6, 11.8 and 4.4 Hz); 1.43- Alkylation/ R_(t) = 2.5 min. 1.54 (4 H, m); 1.71-1.85 (3 H, m); 1.93-2.09 (4 H, m); 2.10 (6 H, s); 45% 2.34 (2 H, s); 3.05-3.12 (4 H, m); 3.32 (2 H, dt, J = 11.7 and 2.2 Hz); 3.91-3.97 (2 H, m); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 30.7; 32.7; 32.9; 33.7; 35.8; 38.1; 43.3; 48.3; 59.6; 59.9; 67.5; 123.5; 125.0; 126.3, 174.1. 140 2 Ex. no. 24b/ [M + H]⁺ = 377.2, ¹H-NMR (CDCl₃): 1.40-1.61 (5 H, m); 1.70-1.80 (2 H, m); 1.91-2.09 Alkylation/ low UV activity (5 H, m); 2.10 (6 H, s); 2.11-1.26 (1 H, m); 2.32 (2 H, s); 3.05 (2 H, 42% s); 3.24 (2 H, t, J = 7.4 Hz); 3.32 (1 H, dd, J = 8.3 and 6.9 Hz); 3.72 (1 H, dd, J = 15.4 and 7.7 Hz); 3.79-3.90 (2 H, m); 6.84 (1 H, dd, J = 3.5 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 0.9 Hz). ¹³C-NMR (CDCl₃): 30.7; 32.2; 32.7; 32.72; 32.9; 35.6; 36.9; 38.1; 141 41.3; 43.7; 58.6; 59.5; 67.8; 73.1; 123.5; 125.0; 126.2; 173.6. 1 Ex. no. 24a/ [M + H]⁺ = 377.2, ¹H-NMR (CDCl₃): 1.41-1.70 (5 H, m); 1.72-1.81 (2 H, m); 2.00-2.09 Alkylation/ low UV activity (4 H, m); 2.10 (6 H, s); 2.11-1.18 (2 H, m); 2.19 (2 H, s); 3.20 (2 H, 49% s); 3.28 (2 H, t, J = 7.4 Hz); 3.36 (1 H, dd, J = 8.3 and 6.9 Hz); 3.71- 3.78 (1 H, m); 3.82-3.93 (2 H, m); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): ): 30.7; 32.2; 32.7; 32.79; 35.6; 36.1; 36.9; 38.1; 41.4; 44.2; 58.1; 59.2; 67.9; 73.1; 123.5; 124.8; 126.3; 173.6. 142 1 Ex. no. 24a/ [M + H]⁺ = 363.2, ¹H-NMR (CDCl₃): 1.43-1.51 (2 H, m); 1.57-1.67 (2 H, m); 1.73-1.82 Alkylation/ low UV activity (2 H, m); 1.95-2.09 (4 H, m); 2.10 (6 H, s); 2.20 (2 H, s); 2.47-2.56 25% (1 H, m); 3.19-3.26 (3 H, m); 3.36 (1 H, dd, J = 13.6 and 7.6 Hz); 3.47 (1 H, dd, J = 8.6 and 6.3 Hz); 3.76 (1 H, td, J = 8.5 and 7.3 Hz); 3.82-3.91 (2 H, m); 6.85 (1 H, dd, J = 3.5 and 0.9 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, dd, J = 5.0 and 0.8 Hz). ¹³C-NMR (CDCl₃): 30.1; 32.6; 32.8; 35.8, 38.0; 38.1; 44.0; 45.3; 58.8; 59.2; 67.7; 71.4; 123.5; 124.8; 126.3; 174.0. 143 2 Ex. no. 24b/ [M + H]⁺ = 363.2, ¹H-NMR (CDCl₃): 1.40-1.51 (2 H, m); 1.52-1.62 (1 H, m); 1.70-1.79 Alkylation/ low UV activity (2 H, m); 1.89-2.09 (5 H, m); 2.10 (6 H, s); 2.32 (2 H, s); 2.42-2.50 22% (1 H, m); 3.07 (2 H, s); 3.18 (1 H, dd, J = 13.7 and 7.5 Hz); 3.31 (1 H, dd, J = 13.7 and 7.6 Hz); 3.42 (1 H, dd, J = 8.6 and 6.2 Hz); 3.68-3.88 (3 H, m); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 30.1; 32.7; 32.8; 35.8; 37.9; 38.1; 43.5; 45.2; 59.2; 59.5; 67.6; 71.3; 123.5; 125.0; 126.3; 174.0. 144 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.87 (2 H, m); 1.26 (2 H, m); 1.44-1.52 (2 H, m); Alkylation/ 327.2 (95%) 1.70 (2 H, t, J = 7.0 Hz); 1.76-1.84 (2 H, m); 1.96-2.09 (4 H, m); 49% [M + H]⁺ = 372.2 2.10 (6 H, s); 2.21 (2 H, s); 3.31 (2 H, s); 3.48 (2 H, t, J = 7.1 Hz); (100%), R_(t) = 2.3 6.85 (1 H, dd, J = 3.6 and 0.8 Hz); 7.04 (1 H, dd, J = 5.0 and 3.6 min. Hz); 7.24 (1 H, dd, J = 5.1 and 0.7 Hz). ¹³C-NMR (CDCl₃): 7.6; 14.1; 32.6; 32.7; 35.7; 38.0; 41.2; 44.0; 59.2; 123.0; 123.4; 124.8; 126.3; 174.1. 145 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.85 (2 H, m); 1.23 (2 H, m); 1.49 (2 H, ddd, J = Alkylation/ 327.2 (100%) 13.2, 9.1 and 4.0 Hz); 1.66 (2 H, t, J = 7.1 Hz); 1.72-1.80 (2 H, m); 50% [M + H]⁺ = 372.2 1.92-2.09 (4 H, m); 2.10 (6 H, s); 2.33 (2 H, s); 3.16 (2 H, s); 3.44 (2 (90%), R_(t) = 2.5 H, t, J = 7.1 Hz); 6.84 (1 H, dd, J = 3.6 and 1.1 Hz); 7.04 (1 H, dd, min. J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 7.5; 14.0; 32.5; 32.7; 32.9; 35.7; 38.1; 41.1; 43.4; 59.5; 122.9; 123.5; 125.0; 126.3; 174.1. 146 1 Ex. no. 24a/ [M + H]⁺ = 349.2, ¹H-NMR (CDCl₃): 1.42-1.53 (2 H, m); 1.73-1.85 (3 H, m); 1.97-2.08 Alkylation/ R_(t) = 2.1 min. (3 H, m); 2.09 (6 H, s); 2.21 (2 H, d, J = 2.8 Hz); 2.41-2.52 (1 H, m); 51% 2.62-2.70 (1 H, m); 3.34 (1 H, d, J = 10.1 Hz); 3.44-3.57 (3 H, m); 4.46-4.53 (1 H, m); 4.62-4.69 (1 H, m); 4.93-5.00 (1 H, m); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.23 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 24.8; 32.6; 32.84; 32.7; 35.8; 38.0; 43.8; 48.1; 59.3; 60.0; 68.5; 81.3; 123.4; 124.8; 126.2; 142.8; 174.3. 147 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.41-1.56 (2 H, m); 1.64-1.83 (3 H, m); 1.90-2.09 Alkylation/ 304.2, R_(t) = 2.3 (3 H, m); 2.10 (6 H, s); 2.35 (2 H, d, J = 5.0 Hz); 2.39-2.49 (1 H, m); 32% min. 2.58-2.60 (1 H, m); 3.20 (1 H, d, J = 10.0 Hz); 3.32 (1 H, d, J = 10.0 Hz); 3.42-3.53 (2 H, m); 4.41-4.48 (1 H, m); 4.59-4.65 (1 H, m); 4.90-4.97 (1 H, m); 6.83 (1 H, dd, J = 3.5 and 1.1 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.23 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 24.8; 32.66; 32.7; 32.8; 35.9; 38.1; 43.4; 48.1; 59.5; 60.4; 68.5; 81.5; 123.4; 124.9; 126.2; 142.7; 174.3. 148 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.40-1.50 (2 H, m); 1.67 (1 H, br s); 1.70-1.80 (2 Alkylation/ 304.2 (100%) H, m); 1.93-2.09 (3 H, m); 2.10 (6 H, s); 2.18 (2 H, s); 3.16 (2 H, s); 44% [M + H]⁺ = 349.3 3.17-3.25 (1 H, m); 3.59 (2 H, d, J = 7.2 Hz); 4.46 (2 H, t, J = 6.2 (100%), R_(t) = 2.0 Hz); 4.78 (2 H, dd, J = 7.8 and 6.2 Hz); 6.84 (1 H, dd, J = 3.6 and min. 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.25 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 32.6; 32.7; 34.1; 35.9; 38.0; 43.9; 45.4; 59.2; 75.4; 123.5; 124.8; 126.3; 174.0. 149 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.40-1.49 (2 H, m); 1.62-1.77 (3 H, m); 1.90-2.09 Alkylation/ 304.2 (100%) (3 H, m); 2.10 (6 H, s); 2.32 (2 H, s); 3.01 (2 H, s); 3.13-3.21 (1 H, 48% [M + H]⁺ = 349.2 m); 3.55 (2 H, d, J = 7.2 Hz); 4.42 (2 H, t, J = 6.2 Hz); 4.74 (2 H, dd, (100%), R_(t) = 2.2 J = 7.8 and 6.2 Hz); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.04 (1 H, min. dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 32.7; 32.8; 34.0; 35.9; 38.1; 43.2; 45.4; 59.5; 75.4; 123.5; 125.0; 126.3; 174.0. 150 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.43-1.51 (2 H, m); 1.74-1.83 (2 H, m); 1.93-1.98 Alkylation/ 346.3 (95% (2 H, m); 1.99-2.07 (4 H, m); 2.10 (6 H, s); 2.11-2.27 (6 H, m); 58% [M + H]⁺ = 386.3 2.49-2.59 (2 H, m); 3.25 (2 H, s); 3.38-3.41 (2 H, m); 6.84 (1 H, dd, (100%), R_(t) = 2.5 J = 3.5 and 0.9 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, min. dd, J = 5.1 and 0.9 Hz). ¹³C-NMR (CDCl₃): 16.8; 32.1; 32.7; 33.8; 34.8; 35.6; 38.0; 39.0; 44.0; 58.5; 59.2; 123.4; 124.1; 124.8; 126.3; 174.0. 151 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.43-1.52 (2 H, m); 1.72-1.80 (2 H, m); 1.89-1.94 Alkylation/ 341.2 (100%) (2 H, m); 1.95-2.07 (4 H, m); 2.11 (6 H, s); 2.12-2.23 (4 H, m); 2.33 85% [M + H]⁺ = 386.3 (2 H, s); 2.47-2.56 (2 H, m); 3.11 (2 H, s); 3.33-3.38 (2 H, m); 6.85 (85%), R_(t) = 2.7 (1 H, dd, J = 3.6 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); min. 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 16.8; 32.1; 32.7; 32.9; 33.8; 34.8; 35.7; 38.1; 39.0; 59.0; 59.6; 123.5; 124.1; 125.0; 126.3; 174.0. 154 2 Ex. no. 153/ [M + H]⁺ = 307.3, ¹H-NMR (CDCl₃): 1.42-1.51 (2 H, m); 1.66-1.79 (2 H, m); 1.82-2.09 Alkylation/ R_(t) = 2.2 min. (4 H, m); 2.11 (6 H, s); 2.17 (2 H, s); 2.47 (3 H, d, J = 1.1 Hz); 2.82 64% (3 H, s); 3.20 (2 H, s); 6.51 (1 H, d, J = 3.5 Hz); 6.66-6.69 (1 H, m). ¹³C-NMR (CDCl₃): 15.2; 29.7; 32.6; 33.0; 35.3; 38.1; 44.1; 59.4; 60.5; 124.5; 124.9; 137.9; 173.8. 155 1 Ex. no. 152/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.43-1.52 (2 H, m); 1.68-1.76 (2 H, m); 1.85-2.09 Alkylation/ 262.3 (100%) (4 H, m); 2.10 (6 H, s); 2.30 (2 H, s); 2.46 (3 H, d, J = 1.1 Hz); 2.79 63% [M + H]⁺ = 307.3 (3 H, s); 3.05 (2 H, s); 6.60 (1 H, d, J = 3.5 Hz); 6.66-6.68 (1 H, m). (10%), R_(t) = 2.4 ¹H-NMR (CDCl₃): 15.2, 29.6; 32.6; 33.1; 35.4; 38.2; 43.3; 59.6; 61.2; min. 124.4; 124.9; 137.8; 173.8. 156 2 Ex. no. 153/ [M + H]⁺ = 349.4, ¹H-NMR (CDCl₃): 0.92 (3 H, t, J = 7.3 Hz); 1.25-1.36 (2 H, m); 1.43- Alkylation/ R_(t) = 2.6 min. 1.52 (4 H, m); 1.68-1.77 (2 H, m); 1.85-2.10 (4 H, m); 2.11 (6 H, s); 68% 2.18 (2 H, s); 2.46 (3 H, d, J = 1.1 Hz); 3.19 (2 H, s); 3.25 (2 H, t, J = 7.3 Hz); 6.61 (1 H, d, J = 3.5 Hz); 6.66-6.69 (1 H, m). ¹³C-NMR (CDCl₃): 13.8; 15.2; 20.0; 29.3; 32.7; 32.8; 35.5; 38.1; 42.0; 44.5; 57.8; 59.4; 124.5; 124.9; 137.8; 173.6. 157 1 Ex. no. 152/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.3 Hz); 1.22-1.33 (2 H, m); 1.39- Alkylation/ 304.3 (100%) 1.51 (4 H, m); 1.66-1.76 (2 H, m); 1.86-2.09 (4 H, m); 2.10 (6 H, s); 68% [M + H]⁺ = 349.4 2.31 (2 H, s); 2.46 (3 H, d, J = 1.0 Hz); 3.04 (2 H, s); 3.21 (2 H, t, J = (10%), R_(t) = 3.0 7.3 Hz); 6.60 (1 H, d, J = 3.5 Hz); 6.65-6.68 (1 H, m). min. ¹³C-NMR (CDCl₃): 13.7; 15.2; 20.0; 29.3; 32.6; 32.9; 35.8; 38.2; 42.0; 43.6; 58.7; 59.6; 124.4; 124.9; 137.8; 173.6. 158 2 Ex. no. 153/ [M + H]⁺ = 375.4, ¹H-NMR (CDCl₃): 1.16-1.27 (2 H, m); 1.42-1.80 (11 H, m); 1.84- Alkylation/ R_(t) = 2.9 min. 2.20 (12 H, m); 2.48 (3 H, s); 3.19 (2 H, d, J = 7.8 Hz); 3.24 (2 H, br 13% s); 6.63 (1 H, br s); 6.70 (1 H, br s). ¹³C-NMR (CDCl₃): 15.3; 25.1; 30.4; 32.3, 32.7; 35.5; 38.0; 47.4; 124.7; 173.6 . . All the other signals could not be identified due to a low sample concentration. 159 1 Ex. no. 152/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.11-1.22 (2 H, m); 1.42-1.76 (10 H, m); 1.85- Alkylation/ 330.3 (100%) 1.97 (2 H, m); 2.00-2.09 (3 H, m); 2.10 (6 H, s); 2.31 (2 H, s); 2.46 32% [M + H]⁺ = 375.4 (3 H, d, J = 1.0 Hz); 3.06 (2 H, s); 3.15 (2 H, d, J = 7.8 Hz); 6.61 (1 (10%), R_(t) = 3.2 H, d, J = 3.5 Hz); 6.65-6.88 (1 H, m). min. ¹³C-NMR (CDCl₃): 15.2; 25.1; 30.4; 32.6; 32.9; 35.7; 38.0; 38.2; 43.5; 47.4; 59.1; 59.7; 126.4; 125.0; 137.8; 173.8. 160 1 Ex. no. 152/ [M + H]⁺ = 347.3, ¹H-NMR (CDCl₃): 0.12-0.18 (2 H, m); 0.43-0.49 (2 H, m); 0.77-0.87 Alkylation/ R_(t) = 2.9 min. (1 H, m); 1.43-1.52 (2 H, m); 1.68-1.77 (2 H, m); 1.85-2.08 (4 H, 66% m); 2.10 (6 H, s); 2.31 (2 H, s); 2.45 (3 H, s); 3.08 (2 H, d, J = 7.1 Hz); 3.14 (2 H, s); 6.60 (1 H, d, J = 3.4 Hz); 6.65-6.69 (1 H, m). ¹³C-NMR (CDCl₃): 3.4; 9.0; 15.2; 32.5; 32.9; 35.6; 38.1; 43.5; 46.9; 58.8; 59.6; 124.4; 124.9; 137.8; 173.4. 161 1 Ex. no. 152/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.40-1.49 (2 H, m); 1.65-1.75 (4 H, m); 1.80-2.10 Alkylation/ 316.3 (100%) (8 H, m); 2.11 (6 H, s); 2.30 (2 H, s); 2.42-2.51 (1 H, m); 2.47 (3 H, 69% [M + H]⁺ = 361.3 d, J = 1.0 Hz); 3.01 (2 H, s); 3.25 (2 H, d, J = 7.6 Hz); 6.61 (1 H, d, (10%), R_(t) = 3.1 J = 3.5 Hz); 6.66-6.69 (1 H, m). min. ¹³C-NMR (CDCl₃): 15.2; 18.4; 18.5; 24.8; 26.4; 26.5; 32.6; 32.8; 33.9; 35.7; 38.2, 43.4; 47.8; 59.0; 59.7; 124.4; 124.9; 137.8; 173.7. 163 2 Ex. no. 162 [M + H]⁺ = 329.4, ¹H-NMR (CDCl₃): 0.93 (3 H, t, J = 7.3 Hz); 1.27-1.42 (4 H, m); 1.45- Step 3/ R_(t) = 2.4 min. 1.53 (2 H, m); 1.70-1.78 (2 H, m); 1.85-2.20 (2 H, m); 2.03 (6 H, s); Alkylation/ 2.13 (2 H, s); 2.14-2.25 (2 H, m); 3.23 (2 H, s); 3.26 (2 H, t, J = 7.3 87% Hz); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 13.8; 20.0; 29.4; 30.2; 32.9; 35.7; 38.0; 42.1; 44.6; 57.9; 60.2; 126.7; 127.4; 127.8; 173.6. 164 1 Ex. no. 431/ [M + H]⁺ = 329.4, ¹H-NMR (CDCl₃): 0.88 (3 H, t, J = 7.3 Hz); 1.22-1.46 (6 H, m); 1.66- Alkylation/ R_(t) = 2.9 min. 1.75 (2 H, m); 1.85-2.00 (2 H, m); 2.03 (6 H, s); 2.15-2.31 (2 H, m); 61% 2.35 (2 H, s); 2.97 (2 H, s); 3.20 (2 H, t, J = 7.3 Hz); 7.24-7.32 (3 H, m); 7.35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 13.7; 20.0; 29.3; 30.1; 30.11; 30.2; 30.25; 32.9; 33.0; 35.8; 38.0; 41.9; 43.6; 58.9; 60.5; 126.6; 126.7; 127.6; 127.7; 136.4; 173.6. 165 2 Ex. no. 162 [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.14-1.27 (2 H, m); 1.33-1.43 (2 H, m); 1.50-1.80 Step 3/ R_(t) = 2.7 min. (9 H, m); 1.90-2.20 (2 H, m); 2.03 (6 H, s); 2.08-2.20 (4 H, m); 3.19 Alkylation/ (2 H, d, J = 7.8 Hz); 3.26 (2 H, s); 7.27-7.31 (3 H, m); 7.35-7.41 (2 26% H, m). ¹³C-NMR (CDCl₃): 25.1; 30.2; 30.5; 32.8; 35.8; 38.0; 38.1; 44.5; 47.4; 58.3; 60.1; 126.7; 127.4; 127.7; 173.8. 166 1 Ex. no. 431 [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.10-1.20 (2 H, m); 1.30-1.40 (2 H, m); 1.42-1.75 Alkylation/ R_(t) = 3.1 min. (8 H, m); 1.84-2.20 (3 H, m); 2.02 (6 H, s); 2.10-2.30 (2 H, br s); 27% 2.35 (2 H, s); 3.00 (2 H, s); 3.11 (2 H, d, J = 7.8 Hz); 7.24-7.31 (3 H, m); 7.34-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 25.1; 30.0; 30.2, 30.3; 33.0; 35.9; 37.9; 38.0; 43.6; 47.3; 59.2; 60.4; 126.6; 127.5; 127.7; 173.7. 167 2 Ex. no. 162 [M + H]⁺ = 369.4, ¹H-NMR (CDCl₃): 1.30-1.39 (2 H, m); 1.65-1.73 (2 H, m); 1.80-195 Step 3/ R_(t) = 2.5 min. (2 H, m); 2.00 (6 H, s); 2.13-2.25 (2 H, m); 2.16 (2 H, s); 3.20 (2 H, Alkylation/ s); 4.62 (2 H, s); 6.95-6.98 (2 H, m); 7.23-7.30 (4 H, m); 7.35-7.40 58% (2 H, m). ¹³C-NMR (CDCl₃): 30.2; 32.7; 35.7; 38.0; 41.0; 44.6; 56.9; 60.1; 125.5; 126.72; 126.74; 126.8; 127.4; 127.8; 139.0; 173.4. 167 2 Ex. no. 162 [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 0.03-0.09 (2 H, m); 0.43-0.49 (2 H, m); 0.59-0.70 Step 3/ R_(t) = 2.5 min. (1 H, m); 1.33-1.45 (4 H, m); 1.69-1.78 (2 H, m); 1.85-2.01 (2 H, Alkylation/ m); 2.03 (6 H, d, J = 1.3 Hz); 2.13 (2 H, s); 2.15-2.26 (2 H, m); 3.26 45% (2 H, s); 3.34 (2 H, t, J = 7.2 Hz); 7.27-7.31 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 4.7; 8.9; 30.6; 32.8; 33.4; 36.0; 38.3; 43.0; 44.9; 58.6; 60.4; 127.0; 127.7; 128.0; 173.9. 168 1 Ex. no. 431/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 0.01-0.04 (2 H, m); 0.38-0.44 (2 H, m); 0.54-0.64 Alkylation/ R_(t) = 2.9 min. (1 H, m); 1.30-1.40 (4 H, m); 1.66-1.76 (2 H, m); 1.85-2.00 (2 H, 50% m); 2.03 (6 H, s); 2.16-2.32 (2 H, m); ); 2.36 (2 H, s); 3.01 (2 H, s); 3.38 (2 H, t, J = 7.2 Hz); 7.24-7.32 (3 H, m); 7.34-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 4.3; 8.6; 30.1; 32.4; 33.1; 35.8; 38.1; 42.6; 43.7; 59.2; 60.6; 126.6; 127.6; 127.7; 173.6. 169 2 Ex. no. 162 [M + H]⁺ = 341.3, ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.65-1.79 (5 H, m); 1.85-1.95 Step 3/ R_(t) = 2.5 min. (3 H, m); 2.03 (6 H, s); 2.03-2.09 (2 H, m); 2.12 (2 H, s); 2.12-2.27 Alkylation/ (2 H, m); 2.53 (1 H, td, J = 15.6, 7.8 Hz); 3.20 (2 H, s); 3.29 (2 H, d, 64% J = 7.6 Hz); 7.26-7.30 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 18.4; 26.4; 30.3; 32.8; 34.0; 35 8; 38.0; 44.3; 47.9; 58.1; 60.1; 126.7; 127.4; 127.7; 173.7. 170 1 Ex. no. 431/ [M + H]⁺ = 341.5, ¹H-NMR (CDCl₃): 1.30-1.40 (2 H, m); 1.60-1.73 (4 H, m); 1.80-2.02 Alkylation/ R_(t) = 3.0 min, (6 H, m); 2.03 (6 H, s); 2.15-2.33 (2 H, m); 2.35 (2 H, s); 2.45 (1 H, 45% td, J = 15.6, 7.8 Hz); 2.95 (2 H, s); 3.24 (2 H, d, J = 7.6 Hz); 7.27- 7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 18.3; 26.3; 30.1; 33.0; 33.8; 36.0; 38.1; 43.5; 47.8; 59.3, 60.5; 126.6; 127.6; 127.7; 173.7. 171 2 Ex. no. 162 [M + H]⁺ = 327.4, ¹H-NMR (CDCl₃): 0.18-0.23 (2 H, m); 0.49-0.55 (2 H, m); 0.83-0.94 Step 3/ R_(t) = 2.3 min. (1 H, m); 1.35-1.43 (2 H, m); 1.71-1.79 (2 H, m); 1.85-2.02 (2 H, Alkylation/ m); 2.04 (6 H, s); 2.13 (2 H, s); 2.16-2.30 (2 H, m); 3.13 (2 H, d, J = 56% 7.1 Hz); 3.35 (2 H, s); 7.26-7.31 (3 H, m); 7.36-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 3.4; 9.1; 30.3; 32.9; 35.8; 38.0; 44.6; 47.0; 57.9; 60.2; 126.7; 127.5; 127.7; 173.4. 172 1 Ex. no. 431/ [M + H]⁺ = 327.4, ¹H-NMR (CDCl₃): 0.11-0.16 (2 H, m); 0.42-0.47 (2 H, m); 0.75-0.85 Alkylation/ R_(t) = 2.8 min. (1 H, m); 1.32-1.41 (2 H, m); 1.67-1.76 (2 H, m); 1.87-2.00 (2 H, 58% m); 2.03 (6 H, s); 2.15-2.33 (2 H, m); 2.36 (2 H, s); 3.05-3.10 (4 H, m); 7.24-7.31 (3 H, m); 7.35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 3.3; 9.0; 30.1; 33.0; 35.9; 38.0; 43.5; 46.9; 59.0; 60.4; 126.6; 127.5; 127.7; 173.4. 173 2 Ex. no. 162 [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.33-142 (2 H, m); 1.56-1.68 (5 H, m); 1.68-2.02 Step 3/ R_(t) = 2.7 min. (6 H, m); 2.03 (6 H, s); 2.04-2.10 (2 H, m); 2.12 (2 H, s); 2.13-2.30 Alkylation/ (2 H, m); 3.14-3.20 (2 H, m); 3.22 (2 H, s); 7.26-7.31 (3 H, m); 60% 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 18.6; 28.2; 30.2; 32.9; 33.7; 34.3; 35.6 38.0; 40.5; 44.6; 58.0; 60.1; 126.7; 127.4; 127.7, 173.5. 174 1 Ex. no. 431/ [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.31-1.40 (2 H, m); 147-153 (4 H, m); 1.66-1.85 Alkylation/ R_(t) = 3.2 min. (5 H, m); 188-2.02 (3 H, m); 2.03 (6 H, s); 2.14-2.30 (3 H, m); 2.35 51% (2 H, s); 2.97 (2 H, s); 3.08-3.14 (2 H, m); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 18.5; 28.2; 30.1; 33.1; 33.6; 34.2; 35.8; 38.1; 40.4; 43.7, 59.0; 60.5; 126.6; 127.6; 127.7; 173.5. 175 2 Ex. no. 162 [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.87 (2 H, dd, J = 5.1 Hz); 1.26 (2 H, dd, J = 5.0 Step 3/ 321.3 (20%) Hz); 135-1.44 (2 H, m); 1.71 (2 H, t, J = 7.1 Hz); 1.74-1.82 (2 H, Alkylation/ [M + H]⁺ = 366.3 m); 2.03 (8 H, s); 2.10-2.21 (4 H, s); 3.35 (2 H, s); 3.48 (2 H, t, J = 47% (100%), R_(t) = 2.3 7.1 Hz); 7.29 (3 H, d, J = 7.5 Hz); 7.35-7.41 (2 H, m). min. ¹³C-NMR (CDCl₃): 7.6; 14.1; 30.1; 32.6; 32.9; 35.8; 38.0; 41.2; 44.2; 58.9; 60.1; 123.0; 126.7; 127.4; 127.7; 174.2. 176 1 Ex. no. 431/ [MH-HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.84 (2 H, dd, J = 5.2 Hz); 1.22 (2 H, dd, J = 4.9 Alkylation/ 321.3 (25%) Hz); 1.34-1.42 (2 H, m); 1.65 (2 H, t, J = 7.1 Hz); 169-1.77 (2 H, 54% [M + H]⁺ = 366.3 m); 187-2.00 (2 H, m); 2.03 (6 H, s); 2.18-2.33 (2 H, m); 2.37 (2 H, (100%), R_(t) = 2.6 s); 3.10 (2 H, s); 3.42 (2 H, t, J = 7.1 Hz); 7.25-7.31 (3 H, m); 7.35- min. 7.40 (2 H, m). ¹³C-NMR (CDCl₃): 7.5; 14.0; 30.1; 32.5; 33.1; 36.0; 38.0; 41.1; 43.4; 59.9; 60.5; 122.9; 126.7; 127.6; 127.8; 174.2. 177 2 Ex. no. 162 [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.34-1.43 (2 H, m); 1.72-180 (2 H, m); 1.93-1.98 Step 3/ 335.3 (12%) (2 H, m); 1.99-2.07 (3 H, m); 2.03 (6 H, s); 2.11-2.25 (7 H, m); Alkylation/ [M + H]⁺ = 380.3 2.49-2.58 (2 H, m); 3.29 (2 H, s); 3.37-3.41 (2 H, m); 7.27-7.30 (3 58% (100%), R_(t) = 2.3 H, m); 7.35-7.40 (2 H, m). min. ¹³C-NMR (CDCl₃): 16.8; 30.1; 32.1; 32.9; 33.8; 34.9; 35.8; 38.0; 39.0; 44.3; 58.3; 60.2; 124.1; 126.8; 127.4; 127.8; 174.0. 178 1 Ex. no. 431/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.68-1.76 (2 H, m); 1.87-1.92 Alkylation/ 335.3 (20%) (2 H, m); 1.94-2.32 (8 H, m); 2.05 (6 H, s); 2.37 (2 H, s); 2.46-2.55 65% [M + H]⁺ = 380.3 (2 H, m); 3.04 (2 H, s); 3.30-3.36 (2 H, m); 7.28-7.32 (3 H, m); (100%), R_(t) = 2.6 7.36-7.41 (2 H, m). min. ¹³C-NMR (CDCl₃): 16.8; 30.1; 32.1; 33.1; 33.8; 34.8; 38.0; 38.1; 39.0; 43.4; 59.3; 60.5; 124.1; 126.7; 127.6; 127.8; 174.1. 179 2 Ex. no. 162 [M + H]⁺ = 357.3 ¹H-NMR (CDCl₃): 1.37-1.43 (2 H, m); 1.49-1.59 (1 H, m); 1.72-1.81 Step 3/ (100%) (4 H, m); 2.04 (6 H, s); 2.03-2.09 (5 H, m, overlapped); 2.18 (2 H, Alkylation/ [MH − NHMe₂]⁺ = s); 2.12-2.22 (2 H, m, overlapped); 3.44 (2 H, s); 3.46 (2 H, s); 4.09 83% 312.3 (92%), (1 H, s); 7.27-7.31 (3 H, m); 7.37-7.41 (2 H, m). R_(t) = 2.3 min. ¹³C-NMR (CDCl₃): 11.9; 30.1; 32.7; 34.5; 36.7; 38.0; 44.1; 51.7; 61.3; 75.6; 126.9; 127.4; 127.8; 176.3. 180 1 Ex. no. 431/ [M + H]⁺ = 357.3 ¹H-NMR (CDCl₃): 1.35-1.43 (2 H, m); 1.45-1.50 (1 H, m); 1.67-1.77 Alkylation/ (43%) (4 H, m); 2.04 (6 H, s); 2.00-2.08 (5 H, m, overlapped); 2.11-2.33 (2 63% [MH − NHMe₂]⁺ = H, m); 2.41 (2 H, s); 3.20 (2 H, s); 3.38 (2 H, s); 4.06 (1 H, br s); 312.3 (100%), 7.28-7.30 (3 H, m); 7.36-7.40 (2 H, m). R_(t) = 2.5 min. ¹³C-NMR (CDCl₃): 11.9; 30.1; 32.9; 34.5; 36.8; 38.1; 43.2; 51.6; 62.3; 75.6; 126.7; 127.6; 127.8; 176.3. 181 2 Ex. no. 21/ [M + H]⁺ = 345.4, ¹H-NMR (CDCl₃): 1.23 (6 H, s); 1.36-1.46 (2 H, m); 1.72-1.82 (2 H, Alkylation/ R_(t) = 2.2 min. m); 1.90-2.01 (2 H, m); 2.02 (6 H, s); 2.04-2.16 (2 H, m); 2.18 (2 H, 78% s); 3.26 (2 H, s); 3.45 (2 H, s); 3.53 (1 H, br s); 7.26-7.31 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 27.6; 29.9; 30.0; 32.7; 35.8; 36.3; 37.9; 43.9; 55.0; 60.0; 61.4; 71.9; 126.6; 127.3; 127.6; 136.3; 174.6; 175.7. 182 2 Ex. no. 162 [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.18 (6 H, s); 1.32-1.41 (2 H, m); 1.64-1.69 (2 H, Step 3/ 328.3 (72%) m); 1.70-1.77 (2 H, m); 1.91-2.01 (2 H, m); 2.02 (6 H, s); 2.11 (2 H, Alkylation/ [M + H]⁺ = 373.4 s); 2.13-2.27 (2 H, m); 3.20 (3 H, s); 3.25 (2 H, s); 3.29-3.34 (2 H, 55% (100%), R_(t) = 2.5 m); 7.25-7.31 (3 H, m); 7.35-7.41 (2 H, m). min. ¹³C-NMR (CDCl₃): 24.9; 30.2; 32.9; 35.7; 36.7; 38.0; 38.2; 44.6; 49.2; 58.0; 60.2; 73.6; 126.7; 127.4; 127.7; 173.4. 183 1 Ex. no. 431/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.14 (6 H, s); 1.31-140 (2 H, m); 1.57-162 (2 H, Alkylation/ 328.3 (100%) m); 1.67-1.74 (2 H, m); 1.90-2.02 (2 H, m); 2.03 (6 H, s); 2.14-2.29 82% [M + H]⁺ = 373.4 (2 H, m); 2.34 (2 H, s); 3.00 (2 H, s); 3.15 (3 H, s); 3.23-3.29 (2 H, (75%), R_(t) = 2.9 m); 7.25-7.31 (3 H, m); 7.35-7.40 (2 H, m). min. ¹³C-NMR (CDCl₃): 24.8; 30.1; 33.0; 35.8; 36.8; 38.1; 38.1; 43.7; 49.1; 59.1; 60.5; 73.5; 126.6; 127.6; 127.7; 173.5. 184 2 Ex. no. 162 [M + H]⁺ = 385.4 ¹H-NMR (CDCl₃) 1.32-1.44 (2 H, m); 1.52-1.66 (1 H, m); 1.69-1.80 Step 3/ [MH − HNMe₂]⁺ = (3 H, m); 1.82-1.93 (4 H, m); 1.94-2.02 (2 H, m); 2.03 (6 H, s); Alkylation/ 340.3, R_(t) = 2.5 2.07-2.18 (5 H, m); 2.19-2.31 (1 H, m); 3.15 (3 H, s); 3.23-3.30 (4 47% min. H, m); 7.26-7.32 (3 H, m); 7.34-7.43 (2 H, m). ¹³C-NMR (CDCl₃): 12.4; 30.2; 31.3; 31.8; 32.9; 35.6; 37.8; 38.0; 44.7; 49.3; 58.3; 60.2; 78.2; 126.7; 127.4; 127.7, 173.4. 185 1 Ex. no. 431/ [M + H]⁺ = 385.4 ¹H-NMR (CDCl₃) 1.32-1.41 (2 H, m); 1.54 (1 H, dq, J = 11.6 and Alkylation/ [MH − HNMe₂]⁺ = 8.9 Hz); 1.66-1.75 (3 H, m); 1.76-1.89 (4 H, m); 1.91-2.01 (2 H, 54% 340.3, R_(t) = 2.9 m); 2.03-2.13 (8 H, m); 2.16-2.30 (2 H, m); 2.35 (2 H, s); 3.02 (2 min. H, s); 3.11 (3 H, s); 3.21 (2 H, ddd, J = 15.9, 7.9 and 5.1 Hz); 7.25- 7.32 (3 H, m); 7.35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.4; 30.1; 31.2; 31.9; 33.1; 35.8; 37.7; 38.1; 43.7; 49.3; 59.4; 60.5; 78.2; 126.6; 127.6; 127.7; 136.4; 173.5. 188 1 Ex. no. 71/ [M + H]⁺ = 371.4, ¹H-NMR (CDCl₃): 1.24-1.34 (2 H, m); 1.50-1.68 (5 H, m); 1.78-1.98 Acylation/ R_(t) = 2.7 min. (2 H, m); 2.01 and 2.03 (6 H, 2 s); 2.10-2.23 (2 H, m); 2.29-2.40 (3 57% H, m); 2.64-2.76 (1 H, m); 3.31 (1 H, s); 3.36-3.47 (4 H, m); 3.70- 3.78 (1 H, m); 3.81-3.89 (1 H, m); 3.93-4.00 (1 H, m); 7.24-7.31 (3 H, m); 7.33-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 30.8; 31.1; 31.2; 31.4; 32.3; 35.3; 35.33; 35.8; 37.5; 38.0; 38.04; 38.06; 38.5; 40.3; 42.3; 43.9; 45.0; 55.2; 56.4; 60.7; 67.6; 73.29; 73.31; 126.5; 126.7; 127.5; 127.6; 127.65; 127.7; 135.6; 137.4; 170.39; 170.4. 189 1 Ex. no. 71/ [M + H]⁺ = 343.3, ¹H-NMR (CDCl₃): 1.22-1.35 (2 H, m); 1.54-1.67 (4 H, m); 1.70-2.02 Acylation/ R_(t) = 2.5 min. (2 H, m); 2.03 and 2.04 (6 H, 2 s); 2.05-2.36 (2 H, m); 3.09 (1.2 H, 35% s); 3.20 (0.8 H, t, J = 7.2 Hz); 3.43 (0.8 H, s); 3.49 (1.2 H, t, J = 7.3 Hz); 3.87-3.98 (1 H, m); 4.73-4.83 (2 H, m); 4.91-4.96 (2 H, m); 7.26-7.34 (3 H, m); 7.34-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 30.1; 30.8; 31.0; 31.4; 35.5; 38.0; 38.1; 38.3; 38.5; 40.4; 42.3; 44.16; 44.2; 55.4; 55.7; 60.7; 73.03; 73.04; 126.5; 126.8; 127.5; 127.6; 127.7; 127.8; 169.6; 169.7. 190 1 Ex. no. 71/ [M + H]⁺ = 359.4, ¹H-NMR (CDC₃): 1.25-1.35 (2 H, m); 1.41 and 1.42 (6 H, 2 s); 1.49 Acylation/ R_(t) = 2.8 min. (1 H, t, J = 7.4 Hz); 1.55-1.70 (3 H, m); 1.85-2.03 (2 H, m); 2.04 (6 66% H, s); 2.16-2.34 (2 H, m); 3.18 (1 H, s); 3.20 (2 H, s); 3.46 (0.6 H, s); 3.50 (1.4 H, t, J = 7.2 Hz); 3.66 (1.4 H, s); 3.71 (0.6 H, t, J = 7.0 Hz); 7.26-7.33 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 24.1; 30.2; 30.6; 30.8; 31.7; 34.6; 38.0; 38.1; 38.8; 42.6; 45.3; 45.7; 51.5; 51.6; 56.6; 57.4; 60.8; 79.5; 79.8; 126.5; 126.6; 127.5; 127.6; 127.68; 127.7; 172.6; 172.9. 191 1 Ex. no. 85/ [M + H]⁺ = 327.4, ¹H-NMR (CDCl₃): 0.01-0.06 (2 H, m); 0.38-0.44 (2 H, m); 0.66 (1 H, Reduction/ R_(t) = 1.3 min. m); 1.22-1.32 (2 H, m); 1.34-1.48 (4 H, m); 1.60-1.70 (2 H, m); 100% 1.76-1.94 (2 H, m); 2.02 (8 H, s); 2.26 (2 H, br s); 2.44-2.52 (6 H, m); 7.22-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 4.3; 9.2; 31.0; 34.1; 34.6; 38.1; 38.3; 41.0; 53.9; 56.9; 60.4; 65.6; 70.6; 126.4; 127.4; 127.6; 136.9. 192 1 Ex. no. 86/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): 1.22-1.33 (2 H, m); 1.44 (2 H, t, J = 6.8 Hz); 1.54- Reduction/ R_(t) = 2.2 min. 1.72 (6 H, m); 1.74-1.92 (4 H, m); 1.95-2.08 (2 H, m); 2.02 (6 H, s); 88% 2.20-2.32 (5 H, m); 2.41-2.50 (4 H, m); 7.22-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 18.7; 28.2; 31.1; 34.5; 34.7; 36.0; 38.1; 41.0; 53.8; 54.7; 65.5; 70.6; 126.4; 127.4; 127.6; 136.8. 193 1 Ex. no. 84/ [M + H]⁺ = 343.4, ¹H-NMR (DMSO-d₆): 1.14-1.24 (2 H, m); 1.30 (1 H, t, J = 7.0 Hz); Reduction/ R_(t) = 0.5 min. 1.36 (2 H, t, J = 6.9 Hz); 1.40-1.47 (1 H, m); 1.57-1.67 (4 H, m); 69% 1.90 (6 H, s); 1.82-1.92 (2 H, m, overlapped); 1.94-2.03 (4 H, m); 2.448 (2 H, s); 2.453 (2 H, s); 2.53-2.57 (2 H, m); 4.58 (1 H, br s); 7.21-7.25 (1 H, m); 7.30-7.37 (4 H, m). ¹³C-NMR (DMSO-d₆): 12.0; 26.8; 30.3; 33.8; 33.8; 37.7; 40.7; 54.4; 63.2; 73.4; 126.1; 127.2; 127.3. 194 1 Ex. no. 71/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.24-1.32 (2 H, m); 1.46 (2 H, t, J = 6.9 Hz); 1.63- Reductive 321.3 (100%) 1.70 (2 H, m); 1.79-1.95 (4 H, m); 2.03 (6 H, s); 2.05-2.22 (4 H, m); amination/ [M + H]⁺ = 366.4 2.23-2.34 (2 H, m); 2.48-2.55 (8 H, m); 7.24-7.32 (3 H, m); 7.34- 56% (80%), R_(t) = 0.5 7.39 (2 H, m); min. ¹³C-NMR (CDCl₃): 17.0; 31.1; 32.3; 34.5; 36.7; 38.1; 41.3; 50.8; 52.6; 53.4; 53.8; 60.6; 65.6; 124.5; 126.5; 127.6; 127.7. 195 1 Ex. no. 71/ [M + H]⁺ = 369.4, ¹H-NMR (CDCl₃): 1.24-1.35 (2 H, m); 1.51-1.68 (6 H, m); 1.69-1.76 Acylation/ R_(t) = 3.2 min. (3 H, m); 1.78-1.99 (4 H, m); 2.03 and 2.05 (6 H, 2 s); 2.06-2.17 (3 49% H, m); 2.18-2.40 (3 H, m); 3.32 (1 H, s); 3.32-3.49 (3 H, m); 7.26- 7.33 (3 H, m); 7.34-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 18.28; 18.3; 27.97; 28.0; 30.0; 30.9; 31.2; 31.5; 32.0; 32.1; 32.5; 35.71; 35.74; 36.0; 37.6; 38.0; 38.1; 40.3; 42.3; 43.9; 45.0; 55.2; 56.4; 60.8; 126.5; 126.7; 127.6; 127.63; 127.67; 127.8; 171.98; 172.0. 196 1 Ex. no. 189/ [M + H]⁺ = 329.4, ¹H-NMR (CDCl₃): 1.20-1.30 (2 H, m); 1.41 (2 H, t, J = 6.8 Hz); 1.58- Reduction/ R_(t) = 0.6 min. 1.70 (2 H, m); 1.79-1.99 (2 H, m); 2.01 (6 H, s); 2.10-2.30 (2 H, m); 23% 2.39 (2 H, s); 2.43 (2 H, t, J = 6.8 Hz); 2.72 (1 H, s); 2.74 (1 H, s); 3.12-3.22 (1 H, m); 4.41 (2 H, dd, J = 6.2 and 6.2 Hz); 4.77 (2 H, dd, J = 7.8 and 6.0 Hz); 7.22-7.39 (5 H, m). ¹³C-NMR (CDCl₃): 31.0; 34.5; 34.7; 38.0; 41.2; 53.7; 59.9; 60.4; 65.7; 76.5; 126.4; 126.5; 127.5; 127.6; 127.7. 197 1 Ex. no. 71/ [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 0.02-0.09 (2 H, m); 0.38-0.46 (2 H, m); 0.65-0.78 Acylation/ R_(t) = 3.0 min. (1 H, m); 1.24-1.35 (2 H, m); 1.50-1.70 (6 H, m); 1.80-2.00 (2 H, 76% m); 2.02 and 2.04 (6 H, 2 s); 2.16-2.26 (1 H, m); 2.28-2.40 (3 H, m); 3.32 (1 H, s); 3.40 (1 H, s); 3.45 (2 H, dt, J = 7.3 and 1.9 Hz); 7.25- 7.32 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 4.41; 4.45; 10.5; 10.71; 10.76; 28.5; 30.0; 30.1; 30.5; 30.9; 31.2; 31.4; 34.4; 34.8; 35.9; 37.6; 38.0; 38.1; 40.4; 42.3; 43.9; 45.0; 55.2; 56.4; 60.8; 126.5; 126.7; 127.6; 127.62; 127.66; 127.7; 137.4; 171.87; 171.92. 198 1 Ex. no. 71/ [M + H]⁺ = 352.3, ¹H-NMR (CDCl₃): 1.32 (1 H, dd, J = 10.6 and 3.1 Hz); 1.35 (1 H, dd, Acylation/ R_(t) = 2.6 min. J = 10.6 and 3.1 Hz); 1.45-1.54 (2 H, m); 1.56-1.74 (6 H, m); 1.85- 92% 2.01 (2 H, m); 2.02 and 2.04 (6 H, 2 s); 2.16-2.35 (2 H, m); 3.41 (0.8 H, s); 3.48 (1.2 H, t, J = 7.3 Hz); 3.73 (1.2 H, s); 3.87 (0.8 H, t, J = 7.1 Hz); 7.26-7.32 (3 H, m); 7.35-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 13.2; 13.7; 16.2; 16.6; 30.2; 30.7; 30.8; 31.2; 35.1; 37.6; 38.0; 38.04; 40.1; 42.7; 45.6; 46.0; 57.2; 57.4; 60.7; 120.0; 120.2; 126.6; 126.7; 127.4; 127.5; 127.71; 127.73, 136.0; 137.0; 162.8; 163.0. 199 1 Ex. no. 71/ [M + H]⁺ = 366.3, ¹H-NMR (CDCl₃): 1.28-1.37 (2 H, m); 1.56-1.74 (5 H, m); 1.88-2.00 Acylation/ R_(t) = 2.7 min. (2 H, m); 2.028 and 2.03 (6 H, 2 s); 2.17-2.33 (3 H, m); 2.53-2.69 (2 84% H, m); 2.73-2.82 (2 H, m); 3.38 (1.2 H, s); 3.45 (0.8 H, s); 3.49- 3.55 (2 H, m); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 16.47; 16.5; 30.3; 30.5; 30.56; 30.6; 30.7; 31.4; 34.9; 37.7; 38.0; 38.05; 38.8; 38.98; 40.0; 42.9; 44.9; 45.5; 56.4; 56.9; 60.7; 120.8; 120.9; 126.6; 126.7; 127.5; 127.6; 127.71; 127.75; 137.0; 164.4; 164.7. 200 1 Ex. no. 71/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.79-0.83 (2 H, m); 1.20-1.23 (2 H, m); 1.24-1.32 Reductive 307.3 (100%) (2 H, m); 1.45 (2 H, t, J = 6.9 Hz); 1.60-1.70 (4 H, m); 1.77-1.92 (2 amination/ [M + H]⁺ = 352.4 H, m); 2.02 (6 H, s); 2.16-2.34 (2 H, m); 2.47 (2 H, s); 2.52 (2 H, t, 51% (82%), R_(t) = 0.8 J = 6.9 Hz); 2.62-2.67 (2 H, m); 7.23-7.32 (3 H, m); 7.34-7.39 (2 H, min. m). ¹³C-NMR (CDCl₃): 8.2; 13.9; 31.1; 34.3; 34.5; 38.1; 41.3; 53.8; 54.5; 60.5; 65.5; 123.3; 126.4; 126.5; 127.7. 201 1 Ex. no. 188/ [M + H]⁺ = 357.4, ¹H-NMR (CDCl₃): 1.23-1.32 (2 H, m); 1.45 (2 H, t, J = 6.8 Hz); 1.49- Reduction/ R_(t) = 1.3 min. 1.62 (3 H, m); 1.62-1.70 (2 H, m); 1.80-1.93 (2 H, m); 2.03 (6 H, s); 20% 2.03-2.09 (1 H, m); 2.15-2.31 (3 H, m); 2.34-2.45 (2 H, m); 2.45 (2 H, s); 2.48 (2 H, t, J = 6.8 Hz); 3.33 (1 H, t, J = 7.9 Hz); 3.74 (1 H, dd, J = 15.4 and 7.9 Hz); 3.84 (1 H, dt, J = 8.2 and 4.7 Hz); 3.89- 3.95 (1 H, m); 7.23-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 31.1; 32.4; 32.5; 34.6; 37.8; 38.0; 38.5; 41.08; 53.8; 55.8; 60.5; 65.6; 67.8; 73.4; 126.4; 127.5; 127.7; 136.6. 202 1 Ex. no. 190/ [M + H]⁺ = 345.4, ¹H-NMR (CDCl₃): 1.16 (6 H, s); 1.22-1.30 (2 H, m); 1.46 (2 H, t, J = Reduction/ R_(t) = 2.0 min. 6.9 Hz); 1.63-1.70 (2 H, m); 1.80-1.95 (2 H, m); 2.03 (6 H, s); 2.15- 10% 2.30 (2 H, m); 2.43 (2 H, s); 2.57 (2 H, s); 2.60 (2 H, t, J = 6.9 Hz); 3.21 (3 H, s); 7.23-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 23.6; 30.9; 31.0; 34.2; 38.1; 41.5; 49.3; 55.4; 60.7; 64.5; 67.3; 75.9; 126.4; 127.5; 127.8. 203 1 Ex. no. 195/ [M + H]⁺ = 355.4, ¹H-NMR (CDCl₃): 1.22-1.32 (2 H, m); 1.34-1.48 (6 H, m); 1.52-1.70 Reduction/ R_(t) = 2.7 min. (4 H, m); 1.74-1.90 (4 H, m); 1.98-2.01 (1 H, m); 2.03 (6 H, s); 67% 2.04-2.08 (1 H, m); 2.19-2.38 (5 H, m); 2.46 (2 H, s); 2.48 (2 H, t, J = 6.9 Hz); 7.23-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 18.4; 26.5; 28.3; 31.1; 34.7; 35.0; 36.1; 38.1; 38.4; 41.1; 53.9; 57.1; 60.5; 65.5; 126.4; 127.3; 127.7. 204 1 Ex. no. 197/ [M + H]⁺ = 341.4, ¹H-NMR (CDCl₃): −0.02-0.03 (2 H, m); 0.37-0.43 (2 H, m); 0.60- Reduction/ R_(t) = 2.3 min. 0.70 (1 H, m); 1.18-1.52 (4 H, m); 1.44 (2 H, t, J = 6.8 Hz); 1.54- 72% 1.70 (4 H, m); 1.75-1.95 (2 H, m); 2.03 (6 H, s); 2.15-2.35 (2 H, m); 2.37-2.43 (2 H, m); 2.45-2.51 (4 H, m); 7.24-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 4.4; 10.8; 28.4; 28.9; 31.1; 32.8; 33.7; 34.7, 38.1; 38.3; 41.1; 53.9; 56.8; 56.9; 60.5; 65.6; 126.4; 127.5; 127.7. 205 1 Ex. no. 71/ [M + H]⁺ = 343.3 ¹H-NMR (DMSO-d₆): 0.73-0.81 (2 H, m); 0.91-0.97 (2 H, m); 1.14- Acylation/ (99%) 1.24 (2 H, m); 1.49 (1 H, t, J = 6.9 Hz); 1.54-1.64 (3 H, m); 1.92 (6 59% [MH − NHMe₂]⁺ = H, s); 1.93-2.13 (4 H, m, overlapped); 3.20 (0.8 H, s); 3.26-3.30 298.3 (100%), (1.2 H, m, overlapped by the water signal); 3.63 (1.2 H; s); 3.74- R_(t) = 2.6 min. 3.78 (0.8 H, m); 6.02 (0.3 H, s); 6.08 (0.7 H, s); 7.23-7.28 (1 H, m); 7.32-7.39 (4 H, m). ¹³C-NMR (DMSO-d₆): 13.9, 14.1; 29.1; 30.4; 30.7; 33.9; 36.6; 37.7; 41.6; 44.7; 45.2; 55.4; 56.9; 59.9; 126.2; 127.2; 127.4; 170.5. 206 1 Ex. no. 205/ [M + H]⁺ = 329.3 ¹H-NMR (DMSO-d₆): 0.37 (2 H, dd, J = 6.7 and 4.6 Hz); 0.54 (2 H, Reduction/ (100%) dd, J = 6.9 and 4.6 Hz); 1.16-1.23 (2 H, m); 1.38 (2 H, t, J = 6.9 Hz); 85% [MH − NHMe₂]⁺ = 1.60-1.66 (2 H, m); 1.86-2.08 (4 H, m, overlapped); 1.91 (6 H, s), 284.3 (58%), 2.41 (2 H, s); 2.44 (2 H, s); 2.51-2.53 (2 H, m, overlapped by the R_(t) = 0.3 min. DMSO signal); 4.82 (1 H, s); 7.21-7.26 (1 H, m); 7.30-7.38 (4 H, m). ¹³C-NMR (DMSO-d₆): 12.1; 30.4; 34.0; 37.7; 40.6; 52.8; 53.6; 54.8; 59.5; 63.1; 126.1; 127.2; 127.4. 207 1 Ex. no. 66/ [M + 1]+ = 349.3 ¹H-NMR (DMSO-d₆): 1.25-1.31 (2 H, m); 1.40-1.47 (4 H, m); 1.57- Reduction/ (43%) 1.67 (4 H, m); 1.86-2.02 (6 H, m, overlapped); 1.99 (6 H, s); 2.42 (2 73% [MH − NHMe₂]⁺ = H, s); 2.44 (2 H, s); 2.56 (2 H, t, J = 6.9 Hz); 4.57 (1 H, br s); 6.91 (1 304.3 (100%), H, dd, J = 3.6 and 1.2 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.40 R_(t) = 0.3 min. (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (DMSO-d₆): 12.0; 26.8; 32.9; 33.6; 34.8; 37.7; 40.4; 54.5; 58.7; 63.1; 73.4; 123.4; 124.6; 126.2. 208 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.38 (2 H, ddd, J = 13.2, 9.8 and 3.5 Hz); 1.51 (2 Reductive 327.3 (100%) H, t, J = 6.9 Hz); 1.65-1.73 (2 H, m); 1.86-1.97 (4 H, m); 1.98-2.21 amination/ [M + H]⁺ = 372.3 (2 H, m); 2.10 (6 H, s); 2.45 (2 H, s); 2.47-2.56 (6 H, m); 6.85 (1 H, 40% (15%), R_(t) = 0.4 dd, J = 3.5 and 1.1 Hz); 7.02 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 min. H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 17.0; 32.3; 33.7; 34.3; 34.5; 36.7; 38.1; 41.0; 52.6; 53.9; 59.6; 65.7; 123.3; 124.4; 124.9; 126.1. 209 1 Ex. no. 18/ [M + H]⁺ = 349.3 ¹H-NMR (DMSO-d₆): 0.72-0.80 (2 H, m); 0.91-0.97 (2 H, m); 1.24- Acylation/ (3%) 1.35 (2 H, m); 1.54-1.69 (4 H, m); 1.93-1.99 (4 H, m); 2.01 (6 H, s); 49% [MH − NHMe₂]⁺ = 3.17 (0.8 H, s); 3.28-3.37 (1.2 H, m, overlapped by the water 304.2 (100%), signal); 3.61 (1.2 H; s); 3.75-3.82 (0.8 H, m); 6.06 (1 H, br s); 6.94 R_(t) = 2.5 min. (1 H, dd, J = 3.6 and 1.1 Hz); 7.06 (1 H, dd, J = 5.1 and 3.5 Hz); 7.42 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (DMSO-d₆): 13.9; 14.1; 30.3; 30.4; 32.5; 33.5; 37.7; 41.4; 44.7; 45.3; 57.1; 59.1; 123.6; 124.8; 126.3; 170.5. 210 1 Ex. no. 209/ [M + H]⁺ = 335.3 ¹H-NMR (DMSO-d₆): 0.36 (2 H, dd, J = 6.7 and 4.6 Hz); 0.54 (2 H, Reduction/ (40%) dd, J = 6.9 and 4.6 Hz); 1.26-1.32 (2 H, m); 1.44 (2 H, t, J = 6.8 Hz); 69% [MH − NHMe₂]⁺ = 1.62-1.68 (2 H, m); 1.83-1.97 (4 H, m); 1.99 (6 H, s), 2.41 (4 H, s); 290.3 (100%), 2.51-2.55 (2 H, m, overlapped by the DMSO signal); 4.82 (1 H, s); R_(t) = 0.2 min. 6.91 (1 H, dd, J = 3.5 and 1.1 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.40 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (DMSO-d₈): 12.6; 33.4; 34.2; 36.9; 38.2; 40.9; 53.2; 54.2; 59.2; 63.5; 123.9; 125.2; 128.7. 211 1 Ex. no. 18/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 0.79-0.83 (2 H, m); 1.19-1.23 (2 H, m); 1.38 (2 H, Reductive 313.3 (100%) ddd, J = 13.3, 9.9 and 3.5 Hz); 1.51 (2 H, t, J = 6.9 Hz); 1.60-1.65 (2 amination/ [M + H]⁺ = 358.3 H, m); 1.66-1.73 (2 H, m); 1.84-1.97 (2 H, m); 2.04-2.18 (8 H, m); 45% (10%), R_(t) = 0.7 2.43 (2 H, s); 2.59 (2 H, t, J = 6.9 Hz); 2.61-2.67 (2 H, m); 6.84 (1 H, min. dd, J = 3.6 and 1.1 Hz); 7.03 (1 H, dd, J = 5.1 and 3.6 Hz); 7.22 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 8.2; 13.9; 33.7; 34.3; 37.8; 38.1; 41.0; 53.9; 54.4; 59.6; 65.7; 123.2; 123.3; 124.9; 126.1; 143.2. 212 1 Ex. no. 18/ [M + H]⁺ = 363.3, ¹H-NMR (CDCl₃): 1.33-1.46 (2 H, m); 1.59-1.80 (5 H, m); 1.83-2.07 Acylation/ R_(t) = 2.3 min. (3 H, m); 2.08 and 2.12 (6 H, 2 s); 2.66 (2 H, dd, J = 7.8 and 2.5 Hz); 33% 3.30 (1.2 H, s); 3.33 (0.8 H, s); 3.36-3.50 (3 H, m); 4.40 (0.8 H, dd, J = 6.3 and 2.5 Hz); 4.41 (1.2 H, dd, J = 6.3 and 2.5 Hz); 4.88 (1.2 H, dd, J = 6.3 and 1.4 Hz); 4.90 (0.8 H, dd, J = 6.3 and 1.4 Hz); 6.83-6.87 (1 H, m); 7.01-7.07 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 19.8; 31.1; 31.2; 31.5; 31.6; 32.8; 33.0; 33.4; 35.4; 38.03; 38.07; 38.09; 38.2; 38.5; 40.1; 42.1; 43.9; 45.0; 55.4; 56.4; 59.8; 77.5; 77.54; 123.3; 123.6; 124.9; 125.1; 126.1; 126.4; 169.58; 169.64. 215 2 Ex. no. 24b/ [MH − NHMe₂]⁺ = ¹H-NMR (CDCl₃): 1.44-1.54 (4 H, m); 1.68-1.81 (4 H, m); 1.98-2.68 Alkylation/ 318.2, R_(t) = 2.5 (6 H, m); 2.10 (6 H, s); 2.37 (2 H, s); 3.27 (2 H, s); 3.39 (2 H, s); 79% min. 4.03 (1 H, br. s); ); 6.85 (1 H, dd, J = 3.6 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 11.9; 30.3; 32.7; 34.5; 36.5; 38.1; 43.3; 51.5; 59.5; 60.4; 75.6; 123.5; 125.0; 126.3; 176.2. 216 1 Ex. no. 24a/ [M + 1]+ = 363.3 ¹H-NMR (CDCl₃): 1.46-1.58 (4 H, m); 171-1.83 (4 H, m); 2.04-2.09 Alkylation/ (61%) (6 H, m); 2.10 (6 H, s); 2.23 (2 H, s); 3.42 (2 H, s); 3.43 (2 H, s); 81% [MH − NHMe₂]⁺ = 4.07 (1 H, brs); ); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); 7.05 (1 H, dd, 318.3 (100%), J = 5.1 and 3.6 Hz); 7.25 (1 H, dd, J = 5.1 and 1.0 Hz). R_(t) = 2.2 min. ¹³C-NMR (CDCl₃): 11.9; 32.5; 32.8; 34.5; 36.5; 38.1; 43.8; 51.6; 59.3; 75.6; 123.5, 124.9; 126.3; 176.2. 217 1 Ex. no. 24a/ [M + H]⁺ = 391.3, ¹H-NMR (CDCl₃): 1.47 (2 H, ddd, J = 13.1, 7.6 and 4.9 Hz); 1.54- Alkylation/ R_(t) = 2.5 min. 1.64 (1 H, m); 1.72-1.80 (3 H, m); 1.83-1.93 (4 H, m); 1.99-2.13 52% (12 H, m); 2.17 (2 H, s); 3.15 (3 H, s); 3.22-3.30 (4 H, m); 6.85 (1 H, d, J = 2.9 Hz); 7.05 (1 H, dd, J = 5.1 and 3.6 Hz); 7.25 (1 H, d, J = 4.8 Hz). ¹³C-NMR (CDCl₃): 12.4; 31.2; 31.8; 32.7; 32.8; 35.4; 37.7; 38.0; 44.3; 49.3; 58.3; 59.3; 78.2; 123.4; 124.9; 126.3; 173.3. 218 2 Ex. no. 24b/ [M + H]⁺ = 391.4, ¹H-NMR (CDCl₃): 1.43-1.51 (2 H, m); 1.52-1.62 (1 H, m); 1.68-1.90 Alkylation/ [M − HNMe₂]⁺ = (7 H, m); 1.98-2.14 (12 H, m); 2.31 (2 H, s); 3.09 (2 H, s); 3.12 (3 H, 47% 346.4, R_(t) = 2.8 s); 3.23 (2 H, ddd, J = 16.0, 7.9 and 5.1 Hz); 6.85 (1 H, dd, J = 3.6 min. and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 12.4; 31.2; 31.9; 32.7; 32.9; 35.5; 37.8; 38.1; 43.8; 49.3; 59.1; 59.5; 78.2; 123.5; 125.0; 126.2; 173.4. 219 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.14 (6 H, s); 1.41-1.49 (2 H, m); 1.58-1.63 (2 H, Alkylation/ 334.2 (100%) m); 1.69-1.78 (2 H, m); 1.93-2.08 (4 H, m); 2.09 (6 H, s), 2.30 (2 H, 54% [M + H]⁺ = 379.3 s); 3.06 (2 H, s); 3.15 (3 H, s); 3.25-3.30 (2 H, m); 6.83-6.85 (1 H, (2%), R_(t) = 2.8 m); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22-7.24 (1 H, m). min. ¹³C-NMR (CDCl₃): 24.8; 32.7; 32.8; 35.5; 36.8; 38.1; 38.2; 43.7; 49.1; 58.7; 59.5; 73.5; 123.4; 124.9; 126.2; 142.9; 173.4. 220 1 Ex. no. 24a/ [MH − HNMe₂]⁺ ¹H-NMR (CDCl₃): 1.17 (6 H, s); 1.41-1.49 (2 H, m); 1.63-1.68 (2 H, Alkylation/ 334.2 (100%) m); 1.71-1.79 (2 H, m); 1.93-2.08 (4 H, m); 2.09 (6 H, s); 2.16 (2 H); 70% [M + H]⁺ = 379.3 3.19 (3 H, s); 3.21 (2 H, s); 3.28-3.33 (2 H, m); 6.84 (1 H, dd, J = (55%), R_(t) = 2.5 3.6 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.23 (1 H, dd, min. J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃); 24.9; 32.7; 32.8; 35.5; 36.7; 38.1; 38.2; 44.3; 49.2; 58.1; 59.3; 73.5; 123.4; 124.9; 126.3; 142.5; 173.4. 221 1 Ex. no. 24a/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.23 (6 H, s); 1.38-1.47 (2 H, m); 1.62-1.67 (2 H, Alkylation/ 320.3 (95%) m); 1.73-1.81 (2 H, m); 2.05-2.20 (4 H, m); 2.15 (2 H, s, 37% [M + H]⁺ = 365.3 overlapped); 2.17 (6 H, s, overlapped); 2.52 (1 H, br s); 3.27 (2 H, (100%), R_(t) = 2.3 s); 3.36-3.41 (2 H, m); 6.89 (1 H, dd, J = 3.5 and 0.9 Hz); 7.05 (1 H, min. dd, J = 5.1 and 3.6 Hz); 7.28 (1 H, dd, J = 5.1 and 0.8 Hz). ¹³C-NMR (CDCl₃): 29.5; 32.3; 32.6; 35.5; 37.9; 38.7; 40.0; 44.4; 57.8; 60.5; 69.5; 124.3; 125.7; 126.6; 173.8. 222 2 Ex. no. 24b/ [MH − HNMe₂]⁺ = ¹H-NMR (CDCl₃): 1.21 (6 H, s); 1.41-1.49 (2 H, m); 1.57-1.62 (2 H, Alkylation/ 320.2 (100%) m); 1.70-1.78 (2 H, m); 1.98-2.17 (4 H, m); 2.14 (6 H, s, 56% [M + H]⁺ = 365.3 overlapped); 2.32 (2 H, s); 2.44 (1 H, s); 3.07 (2 H, s); 3.32-3.37 (2 (1%), R_(t) = 2.5 H, m); 6.86-6.89 (1 H, m); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24- min. 7.27 (1 H, m). ¹³C-NMR (CDCl₃): 29.5; 32.4; 32.8; 35.6; 38.0; 38.6; 40.0; 43.4; 58.9; 69.5; 124.0; 125.4; 126.4; 173.9. 223 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (DMSO-d₆): 1.28 (2 H, s); 1.29 (6 H, s); 1.51 (1 H, t, J = 7.4 Acylation; 351.3 (43%) Hz); 1.57-1.67 (3 H, m); 1.93-1.98 (4 H, m); 2.00 (6 H, s); 3.18 (0.7 58% [MH − NHMe₂]⁺ = H, s); 3.33 (1.3 H; t, J = 7.0 Hz, overlapped by the water signal); 306.3 (100%), 3.59 (1.3 H, s); 3.76 (0.7 H, t, J = 6.8 Hz); 5.07 (0.4 H, s); 5.14 (0.6 R_(t) = 2.4 min. H, s); 6.94 (1 H, dd, J = 3.5 and 1.0 Hz); 7.06 (1 H, dd, J = 4.8 and 3.7 Hz); 7.42 (1 H, dd, J = 5.1 and 0.7 Hz). ¹³C-NMR (DMSO-d₆): 27.8; 30.0; 30.6; 32.5; 32.9; 37.7; 38.0; 41.8; 45.5; 45.8; 57.4; 59.0; 59.1; 72.6; 72.8; 123.6; 124.8; 126.3; 142.9; 173.7. 224 2 Ex. no. 24b/ [M + H]⁺ = 351.3, ¹H-NMR (CDCl₃): 1.22 (6 H, s); 1.45-1.54 (2 H, m); 1.77-1.85 (2 H, Alkylation/ R_(t) = 2.2 min. m); 2.00-2.10 (4 H, m); 2.11 (6 H, s); 2.23 (2 H, s); 3.25 (2 H, s); 55% 3.33 (1 H, s); 3.41 (2 H, s); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 27.7; 32.6; 32.7; 36.3; 38.0; 43.8; 55.1; 59.4; 61.4; 72.1; 123.6; 124.9; 126.3; 175.8. 225 1 Ex. no. 24a/ m/z: [MH − ¹H-NMR (CDCl₃): 1.19 (6 H, s); 1.45-1.54 (2 H, m); 1.74-1.83 (2 H, Alkylation/ HNMe₂]⁺ = m); 1.96-2.09 (4 H, m); 2.10 (6 H, s); 2.37 (2 H, s); 3.21 (2 H, s); 71% 306.2, R_(t) = 2.3 3.25 (2 H, s); 3.26 (1 H, s); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.02 min. (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 27.7; 32.6; 32.8; 36.3; 38.1; 43.2; 55.0; 59.6; 62.0; 72.1; 123.5; 125.0; 126.3; 175.8. 226 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.21 (6 H, s); 1.30-1.40 (2 H, m); 1.48-1.52 (2 H, Alkylation/ 351.3, R_(t) = 0.3 m); 1.55-1.60 (2 H, m); 1.60-1.70 (2 H, m); 180-2.05 (3 H, m); Reduction/ min. 2.08 (6 H, s); 2.10 (2 H, s); 2.49 (2 H, s); 2.56-2.61 (2 H, m); 2.70- 2 Steps 27% 2.74 (2 H, m); 6.83 (1 H, dd, J = 3.6 and 1.2 Hz); 7.02 (1 H, dd, J = 5.2 and 3.6 Hz); 7.21 (1 H, dd, J = 5.2 and 1.2 Hz). ¹³C-NMR (CDCl₃): 29.6; 33.6; 33.9; 37.4; 38.1; 38.3; 40.9; 52.7; 53.5; 59.6; 65.5; 71.0; 123.2; 124.8; 126.1. 227 1 Ex. no. 223/ m/z: [M + H]⁺ = ¹H-NMR (DMSO-d₆): 1.04 (6 H, s) 1.20-1.28 (2 H, m); 1.38 (2 H, t, Reduction/ 337.3 (42%) J = 6.9 Hz); 1.57-1.63 (2 H, m); 1.79-1.92 (4 H, m); 1.95 (6 H, s); 79% [MH − NHMe₂]⁺ = 2.25 (2 H, s); 2.41 (2 H, s); 2.54 (2 H, t, J = 7.0 Hz); 3.93 (1 H, s); 292.2 (100%), 6.87 (1 H, dd, J = 3.6 and 1.1 Hz); 7.01 (1 H, dd, J = 5.1 and 3.5 R_(t) = 0.3 min. Hz); 6.87 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (DMSO-d₆): 28.2; 32.9; 33.4; 37.7; 40.6; 55.1; 58.8; 67.2; 69.8; 123.4; 124.6; 126.2. 228 1 Ex. no. 71/ m/z [M + H]⁺ = ¹H-NMR (DMSO-d₆): 1.14-1.24 (2 H, m); 1.28 (2 H, s); 1.30 (4 H, s); Acylation/ 345.4 (100%) 1.44 (1 H, t, J = 7.3 Hz); 1.54-1.64 (3 H, m); 1.91 (6 H, s); 1.95-2.15 74% [MH − NHMe₂]⁺ = (4 H, m); 3.21 (0.7 H, s); 3.30 (1.3 H, t, J = 7.3 Hz, overlapped by 303.3 (73%), the water signal); 3.63 (1.3 H; s); 3.74 (0.7 H, t, J = 7.0 Hz); 5.07 R_(t) = 2.5 min. (0.3 H, s); 5.15 (0.7 H, s); 7.23-7.27 (1 H, m); 7.32-7.39 (4 H, m). ¹³C-NMR (DMSO-d₆): 27.7; 27.8; 29.9; 30.2; 30.8; 33.4; 37.1; 37.7; 38.1; 42.0; 45.4; 45.8; 57.3; 59.8; 59.9; 72.6; 72.8; 126.2; 127.2; 127.4, 136.8, 173.7. 229 1 Ex. no. 228/ m/z: [M + H]⁺ = ¹H-NMR (DMSO-d₆): 1.09 (6 H, s); 1.16-1.24 (2 H, m); 1.35 (2 H, t, Reduction/ 331.3 (100%) J = 6.9 Hz); 1.58-1.65 (2 H, m); 1.90 (6 H, s); 1.92-2.02 (4 H, m); 82% [MH − NHMe₂]⁺ = 2.30 (2 H, s); 2.48 (2 H, s); 2.56 (2 H, t, J = 6.9 Hz); 3.97 (1 H, s); 236.3 (36%), 7.22-7.25 (1 H, m); 7.30-7.37 (4 H, m). R_(t) = 0.3 min. ¹³C-NMR (DMSO-d₆): 28.2; 30.3; 33.7; 37.1; 37.7; 40.8; 55.1; 67.2, 67.7; 69.8; 126.1; 127.2; 127.3; 137.4. 230 2 Ex. no. 162 m/z: [MH − ¹H-NMR (CDCl₃): 1.34-1.43 (8 H, m); 1.72-1.80 (4 H, m); 1.96-2.07 Step 3/ HNMe₂]⁺ = 323.3 (8 H, m); 2.12-2.24 (4 H, m); 3.29 (2 H, s); 3.43-3.49 (2 H, m); Alkylation/ (14%) 7.25-7.30 (3 H, m); 7.35-7.40 (2 H, m). 48% [M + H]⁺ = 368.4 (100%), R_(t) = 2.4 min. 231 1 Ex. no. 431/ m/z: [MH − ¹H-NMR (CDCl₃): 1.33-1.41 (8 H, m); 1.65-1.76 (4 H, m); 1.88-2.01 Alkylation/ HNMe₂]⁺ = 323.3 (2 H, m); 2.04 (6 H, s); 2.15-2.32 (2 H, m); 2.37 (2 H, s); 3.04 (2 H, 60% (20%) s); 3.37-3.42 (2 H, m); 7.25-7.31 (3 H, m); 7.35-7.40 (2 H, m). [M + H]⁺ = 368.4 ¹³C-NMR (CDCl₃): 26.6; 30.0; 30.5; 33.0; 35.9; 37.4; 38.0; 38.9; (100%), R_(t) = 2.7 43.3; 59.0; 60.6; 124.4; 126.7; 127.6; 127.8; 136.2; 173.9. min. 232 1 Ex. no. 71/ m/z: [MH − ¹H-NMR (CDCl₃): 1.27-1.36 (2 H, m); 1.52 (6 H, s); 1.54-1.59 (1.2 Acylation/ HNMe₂]⁺ = 323.3 H, m); 1.62-1.70 (2.8 H, m); 1.82-2.00 (2 H, m); 2.03 (2.4 H, s); 54% (10%) 2.05 (3.6 H, s); 2.14-2.24 (0.8 H, m); 2.31-2.43 (1.2 H, m); 2.48 (0.8 [M + H]⁺ = 368.4 H, s); 2.49 (1.2 H, s); 3.36 (1.2 H, s); 3.43 (0.8 H, s); 3.46 (0.8 H, t, (100%), R_(t) = 2.7 J = 7.2 Hz); 3.50 (1.2 H, t, J = 7.3 Hz); 7.27-7.32 (3 H, m); 7.34-7.42 min. (2 H, m). ¹³C-NMR (CDCl₃): 27.05; 27.11; 30.0; 30.3; 30.4; 30.8; 31.2; 31.3; 35.9; 37.5; 37.95; 38.03; 40.3; 42.5; 43.7; 44.1; 45.4; 55.4; 56.4; 60.8; 61.0; 124.6; 124.7; 126.5; 126.8; 127.58; 127.59; 127.7; 127.8; 135.1; 137.4; 166.9; 167.0. 233 1 Ex. no. 18/ m/z: [MH − ¹H-NMR (CDCl₃): 1.34-1.46 (2 H, m); 1.51 (6 H, s); 1.60-1.64 (1.3 Acylation/ HNMe₂]⁺ = 329.3 H, m); 1.65-1.75 (2.7 H, m); 1.86-2.06 (2.7 H, m); 2.09 (2.4 H, s); 39% (63%) 2.12 (3.6 H, s); 2.17-2.26 (1.3 H, m); 2.48 (2 H, s); 3.32 (1.2 H, s); [M + H]⁺ = 374.3 3.39 (0.8 H, s); 3.45-3.54 (2 H, m); 6.84 (0.4 H, dd, J = 3.8 and 1.1 (100%), R_(t) = 2.6 Hz); 6.86 (0.6 H, dd, J = 3.6 and 1.0 Hz); 7.03 (0.4 H, dd, J = 5.1 min. and 3.6 Hz); 7.05 (0.6 H, dd, J = 5.1 and 3.6 Hz); 7.23 (0.4 H, dd, J = 5.1 and 1.1 Hz); 7.24-7.26 (0.6 H, m). ¹³C-NMR (CDCl₃): 27.05; 27.11; 30.65; 30.44; 31.09; 31.11; 32.8; 33.5; 35.5; 36.9; 38.1; 40.1; 42.3; 43.7; 44.0; 44.08; 44.11; 45.5; 55.7; 56.6; 59.8; 67.7; 123.3; 123.6; 124.6; 124.7; 124.8; 125.2; 126.1; 126.4; 166.8; 166.9. 235 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.35-1.44 (2 H, m); 1.58-1.63 (2 H, m), 1.66-1.76 Acylation/ 391.3 (42%) (4 H, m); 1.81-2.05 (4 H, m); 2.04 (2 H, s); 2.11 (4 H, s); 2.14-2.22 48% [MH − NHMe₂]⁺ = (2 H, m); 2.23-2.34 (2 H, m); 2.58 (0.7 H, s); 2.60 (1.3 H, s); 3.23 (1 346.3 (100%), H, s); 3.24 (2 H, s); 3.37 (0.7 H, s); 3.41 (1.3 H, s), 3.48 (1.3 H, t, J = R_(t) = 2.9 min. 7.2 Hz); 3.54 (0.7 H, t, J = 7.2 Hz); 6.84-6.86 (1 H, m); 7.04 (1 H, ddd, J = 9.7, 5.1 and 3.6 Hz); 7.22-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 12.5; 12.6; 30.5; 30.7; 31.1; 31.2; 32.8; 33.4; 35.8; 37.1; 38.1; 40.1; 40.4; 41.0; 42.0; 43.9; 45.7; 50.19; 50.22; 55.5; 56.9; 59.9; 76.9; 77.2; 77.5; 79.48; 79.50; 123.3; 123.5; 124.8; 125.1; 126.1; 126.3; 169.5; 169.6. 236 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.12-1.36 (4 H, m); 1.38-1.92 (17 H, m); 1.98- Step 347.4, R_(t) = 2.9 2.12 (3 H, m); 2.18-2.30 (2 H, m); 2.25 (8 H, s); 3.06 (2 H, s); 3.15 Alkylation/ min. (2 H, t, J = 7.3 Hz). 77% ¹³C-NMR (CDCl₃): 18.6; 25.1; 26.9; 28.1; 28.5; 31.8; 33.7; 34.3; 36.3; 37.9; 40.3; 42.4; 44.2; 57.7; 60.8; 173.6. 237 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.25-1.33 (2 H, m); 1.51-1.55 (1 H, m); 1.58-1.66 Acylation/ 385.4 (83%) (3 H, m); 1.68-1.79 (1 H, m); 1.81-1.88 (2.6 H, m); 1.91-1.99 (1.4 53% [MH − NHMe₂]⁺ = H, m); 2.03 (2 H, s); 2.04 (4 H, s); 2.11-2.19 (2 H, m); 2.23-2.34 (2 340.3 (100%), H, m); 2.35-2.42 (1 H, m); 2.58 (0.7 H, s); 2.60 (1.3 H, s); 3.23 (1.2 R_(t) = 3.0 min; H, s); 3.25 (1.8 H, s); 3.41 (0.7 H, s); 3.45 (1.3 H, s); 3.46 (1.3 H, t, J = 7.2 H); 3.51 (0.7 H, t, J = 7.2 Hz); 7.27-7.32 (3 H, m); 7.35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.5; 12.6; 30.0; 30.5; 30.7; 30.8; 31.2; 31.4; 36.1; 37.7; 38.0; 38.1; 40.3; 40.4, 41.0; 42.3; 43.9; 45.6; 50.19; 50.22; 55.2; 56.9; 60.8; 76.8; 77.2; 77.5; 79.48; 79.50; 126.5; 126.7; 127.6; 127.66; 127.75; 137.7; 169.5; 169.6. 238 1 Ex. no. 235/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.39 (2 H, ddd, J = 13.4, 10.2 and 3.4 Hz); 1.53 (2 Reduction/ 377.4 (100%) H, t, J = 6.8 Hz); 1.58-1.83 (1 H, m); 1.65-1.89 (4 H, m); 1.83-1.94 79% [MH − NHMe₂]⁺ = (5 H, m); 2.03-2.09 (2 H, m); 2.10 (6 H, s); 2.11-2.19 (2 H, m); 332.3 (38%), 2.39-2.43 (2 H, m); 2.46 (2 H, s); 2.54 (2 H, t, J = 6.8 Hz); 3.12 (3 H, R_(t) = 0.5 min. s); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.23 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 12.5; 28.4; 31.7; 33.3; 33.8; 34.6; 38.2; 40.9; 49.2; 51.3; 54.3; 59.7; 77.5; 78.6; 123.2; 125.0; 126.2. 239 1 Ex. no. 237/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.26-1.32 (2 H, m); 1.47 (2 H, t, J = 6.8 Hz); 1.53- Reduction/ 371.4 (100%) 1.63 (1 H, m); 1.64-1.71 (2 H, m); 1.72-1.80 (2 H, m); 1.84-1.93 (5 78% [MH − NHMe₂]⁺ = H, m); 2.03 (6 H, s); 2.04-2.11 (2 H, m); 2.22-2.36 (2 H, m); 2.40- 326.3 (22%), 2.44 (2 H, m); 2.49-2.55 (4 H, m); 3.13 (3 H, s); 7.25-7.39 (5 H, m). R_(t) = 2.0 min. ¹³C-NMR (CDCl₃): 12.5; 31.2; 31.7; 33.3; 34.7; 38.1; 38.4; 41.2; 49.2; 51.3; 54.2; 60.6; 65.8; 76.8; 77.1; 77.2; 77.4; 78.6; 126.4; 127.6; 127.8. 240 1 Ex. no. 24a/ m/z: [MH − ¹H-NMR (CDCl₃): 1.37 (6 H, s); 1.43-1.51 (2 H, m); 1.67-1.72 (2 H, Alkylation/ HNMe₂]⁺ = 329.3 m); 1.73-1.80 (2 H, m); 1.98-2.18 (4 H, m); 2.14 (6 H, s); 2.34 (2 H, 93% (100%) s); 3.10 (2 H, s); 3.39-3.44 (2 H, m); 6.86-6.89 (1 H, m); 7.05 (1 H, [M + H]⁺ = 374.3 dd, J = 5.1 and 3.6 Hz); 7.25-7.28 (1 H, m). (98%), R_(t) = 2.6 ¹³C-NMR (CDCl₃): 26.6; 30.5; 32.5; 32.9; 35.6; 37.4; 37.9; 38.1; min. 38.9; 43.3; 58.7; 123.9; 124.4; 125.4; 126.4; 173.8. 241 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.42-1.50 (2 H, m); 1.72-1.82 (2 H, m); 1.90 (2 H, Alkylation/ 363.3, R_(t) = 2.2 dd, J = 14.4 and 7.5 Hz); 1.97-2.09 (4 H, m); 2.10 (6 H, s); 2.18 (2 55% min. H, s); 2.90-3.01 (1 H, m); 3.17-3.23 (4 H, m); 4.38 (2 H, t, J = 6.1 Hz); 4.79 (2 H, dd, J = 7.8 and 6.0 Hz); 6.85 (1 H, d, J = 3.2 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 31.2; 32.7; 33.0; 35.5; 38.0; 40.2; 44.1; 58.2; 59.2; 77.3; 123.5; 124.9; 126.3; 174.0. 242 1 Ex. no. 24a/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.42-1.50 (2 H, m); 1.70-1.80 (2 H, m); 1.85 (2 H, Alkylation/ 363.3, R_(t) = 2.4 dd, J = 14.4 and 7.5 Hz); 1.94-2.10 (4 H, m); 2.11 (6 H, s); 2.32 (2 66% min. H, s); 2.90-2.99 (1 H, m); 3.04 (2 H, s); 3.14-3.20 (2 H, m); 4.36 (2 H, t, J = 6.1 Hz); 4.77 (2 H, dd, J = 7.8 and 6.0 Hz); 6.86 (1 H, dd, J = 3.5 and 0.7 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, dd, J = 5.0 and 0.9 Hz). ¹³C-NMR (CDCl₃): 31.2; 32.7; 32.9; 33.0; 35.6; 38.1; 38.1; 40.1; 43.5; 58.8; 77.2; 123.6; 125.1; 126.3; 173.6. 243 1 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.03-0.09 (2 H, m); 0.40-0.48 (2 H, m); 0.64 (1 H, Step 10/ 333.4, R_(t) = 2.9 m); 1.10-1.85 (18 H, m); 2.07 (1 H, m); 2.21 (2 H, s); 2.26 (6 H, s); Alkylation/ min. 3.19 (2 H, s); 3.33 (2 H, t, J = 7.3 Hz). 86% ¹³C-NMR (CDCl₃): 4.2; 8.5; 25.1; 26.9; 28.4; 31.8; 32.3; 35.8; 37.8; 41.0; 42.6; 44.0; 46.9; 56.8; 57.2; 173.8. 244 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.14-1.34 (6 H, m); 1.36-1.62 (6 H, m); 1.62-1.76 Step 9/ 335.4, R_(t) = 2.1 (4 H, m); 2.04 (1 H, m); 2.25 (6 H, s); 2.26 (2 H, s); 3.03 (2 H, s); Alkylation/ min. 3.20 (1 H, m); 3.57 (2 H, d, J = 7.3 Hz); 4.45 (2 H, t, J = 6.1 Hz); 89% 4.76 (2 H, dd, J = 6.1 and 7.7 Hz). ¹³C-NMR (CDCl₃): 25.0; 26.7; 28.5; 31.6; 34.0; 36.7; 37.9; 41.9; 44.1; 45.3, 57.5; 61.4; 75.4; 174.2. 245 2 Ex. no. 234 M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.85 (2 H, m); 1.14-1.36 (8 H, m); 1.38-1.62 (6 H, Step 9/ 358.4, R_(t) = 2.4 m); 1.62-1.80 (6 H, m); 2.04 (1 H, m); 2.26 (6 H, s); 2.28 (2 H, s); Alkylation/ min. 3.18 (2 H, s); 3.45 (2 H, t, J = 7.0 Hz). 59% ¹³C-NMR (CDCl₃): 7.5; 14.0; 25.0; 26.9; 28.3; 31.6; 32.5; 36.3; 37.7; 40.9; 42.0; 44.0; 57.6; 61.8; 122.8, 174.4. 246 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.16-1.36 (6 H, m); 1.38-1.62 (6 H, m); 1.62-1.82 Step 9/ 349.4, R_(t) = 2.2 (4 H, m); 1.87 (2 H, q, J = 7.3 Hz); 2.05 (1 H, m); 2-22-2.30 (2 H, Alkylation/ min. m); 2.26 (6 H, s); 2.96 (1 H, m); 3.06 (2 H, s); 3.18 (2 H, t, J = 7.1 87% Hz); 4.37 (2 H, t, J = 6.1 Hz); 4.77 (2 H, dd, J = 6.2 and 7.6 Hz). ¹³C-NMR (CDCl₃): 25.0; 26.7; 28.5; 31.1; 31.8; 32.9; 36.2; 37.9; 40.0; 41.0; 42.2; 44.0, 57.5; 60.8; 77.3; 173.9. 247 3 Ex. no. 424/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.17-1.37 (6 H, m); 1.41-1.60 (6 H, m); 1.63-2.21 Acylation/ 377.4 (100%) (7 H, m); 2.02-2.21 (5 H, m); 2.24-2.30 (1 H, m, overlapped); 2.26 72% [MH − NHMe₂]⁺ = (6 H, s); 2.570 (1 H, s), 2.575 (1 H, s); 3.221 (1.8 H, s); 3.224 (1.2 H, 332.4 (56%), s); 3.23 (0.8 H, s); 3.26 (1.2 H, s); 3.52 (0.8 H, t, J = 7.3 Hz); 3.56 R_(t) = 2.9 min. (1.2 H, t, J = 7.3 Hz). ¹³C-NMR (CDCl₃): 12.6; 25;1; 25.2; 27.0; 27.1; 28.49; 28.52; 29.78; 29.82; 30.8; 32.1; 33.6; 37.9; 40.3; 40.57; 40.60; 40.61, 42.6; 44.2; 44.3; 44.5; 46.1, 50.21; 50.24; 57.9; 58.8; 61.0; 76.8; 77.16; 77.21; 79.46; 79.52; 169.3; 169.4. 248 1 Ex. no. 18/ m/z: [MH − ¹H-NMR: 1.34-1.42 (2 H, m); 1.37 (6 H, s); 1.51 (2 H, t, J = 6.9 Hz); Reductive HNMe₂]⁺ = 315.2 1.66-1.74 (4 H, m); 1.82-1.97 (2 H, m); 2.06-2.16 (2 H, m); 2.10 (6 Amination/ (100%) H, s); 2.45 (2 H, s); 2.54 (2 H, t, J = 6.9 Hz); 2.56-2.61 (2 H, m); 33% [M + H]⁺ = 360.3 6.84-6.86 (1 H, m); 7.03 (0.4 H, dd, J = 3.6 and 0.4 Hz); 7.04 (0.6 H, (17%), R_(t) = 0.6 dd, J = 3.6 and 0.4 Hz); 7.21-7.24 (1 H, m). min. ¹³C-NMR (CDCl₃): 27.0; 31.2; 33.7; 34.3; 38.1; 39.4; 40.9; 52.7; 53.9; 59.6; 65.6; 123.2; 124.8; 124.9; 126.2. 249 1 Ex. no. 71/ m/z: [MH − ¹H-NMR (CDCl₃): 1.24-1.32 (2 H, m); 1.37 (6 H, s); 1.46 (2 H, t, J = Reductive HNMe₂]⁺ = 309.3 6.8 Hz); 1.63-1.70 (2 H, m); 1.70-1.75 (2 H, m); 1.79-1.95 (2 H, m); amination/ (70%) 2.03 (6 H, s); 2.20-2.35 (2 H, m); 2.49 (2 H, s); 2.53 (2 H, t, J = 6.8 54% [M + H]⁺ = 354.4 Hz); 2.57-2.62 (2 H, m); 7.24-7.34 (3 H, m); 7.35-7.40 (2 H, m). (100%), R_(t) = 0.5 ¹³C-NMR (CDCl₃): 27.0; 31.1; 31.2; 34.5; 38.1; 39.5; 41.2; 52.8; min. 53.8; 60.5; 65.6; 124.8; 126.5; 127.6; 127.7. 250 2 Ex. no. 24b/ m/z: [MH − ¹H-NMR (CDCl₃): 1.40 (6 H, s); 1.42-1.50 (2 H, m); 1.72-1.83 (4 H, Alkylation/ HNMe₂]⁺ = 329.2 m); 2.00-2.11 (4 H, m); 2.12 (6 H, s); 2.19 (2 H, s); 3.27 (2 H, s); 64% (67%) 3.43-3.48 (2 H, m); 6.85-6.87 (1 H, m); 7.05 (1 H, dd, J = 5.1 and [M + H]⁺ = 374.3 3.6 Hz); 7.24-7.26 (1 H, m). (100%), R_(t) = 2.3 ¹³C-NMR (CDCl₃): 26.6; 30.5; 32.7; 35.6; 37.5; 38.0; 39.0; 44.0; min. 58.0; 59.6; 123.6; 124.4; 125.0; 126.4; 173.9. 251 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.33-1.41 (2 H, m); 1.68-1.77 (2 H, m); 1.90-2.02 Step3/ 343.3, R_(t) = 2.1 (2 H, m); 2.03 (6 H, s); 2.12 (2 H, s); 2.13-2.22 (2 H, m); 3.19 (2 H, Alkylation/ min. s); 3.20-3.26 (1 H, m); 3.59 (2 H, d, J = 7.2 Hz); 4.46 (2 H, t, J = 6.2 49% Hz); 4.78 (2 H, dd, J = 7.8 and 6.2 Hz); 7.25-7.31 (3 H, m); 7.35- 7.41 (2 H, m). ¹²C-NMR (CDCl₃): 30.2; 32.7; 34.0; 36.0; 37.9; 44.0; 45.4; 58.7; 60.1; 75.4; 126.8; 127.4; 127.8; 174.0. 252 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.29-1.38 (2 H, m); 1.65-1.73 (2 H, m); 1.85-2.00 Alkylation/ 343.3, R_(t) = 2.3 (2 H, m); 2.03 (6 H, s); 2.15-2.31 (2 H, m); 2.35 (2 H, s); 2.94 (2 H, 55% min. s); 3.10-3.19 (1 H, m); 3.53 (2 H, d, J = 7.2 Hz); 4.40 (2 H, t, J = 6.2 Hz); 4.72 (2 H, dd, J = 7.8 and 6.2 Hz); 7.25-7.31 (3 H, m); 7.35- 7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 32.9; 34.0; 36.2; 38.0; 43.1; 45.3; 59.6; 60.6; 75.3; 126.7; 127.5; 127.8; 136.1; 174.0. 253 1 Ex. no. 18/ [M + H]⁺ = 349.3, ¹H-NMR (CDCl₃): 0.35-0.46 (2 H, m); 0.70-0.74 (2 H, m); 1.32-1.41 Alkylation/ R_(t) = 0.5 min. (2 H, m); 1.53 (2 H, t, J = 7.0 Hz); 1.62-1.74 (4 H, m); 1.90-2.09 (5 2Steps 19% H, m); 2.09 (6 H, s); 2.54 (2 H, s); 2.64 (2 H, t, J = 6.8 Hz); 2.79 (2 H, t, J = 5.5 Hz); 6.84 (1 H, dd, J = 3.5 and 0.8 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.0 and 0.8 Hz). ¹³C-NMR (CDCl₃): 12.8; 33.5; 34.0; 34.3; 37.5; 38.1; 41.0; 53.6; 55.5; 57.7; 59.6; 65.6; 123.2; 124.9; 126.2. 254 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.34-1.43 (2 H, m); 1.70-1.79 (2 H, m); 1.91 (2 H, Step3/ 357.3, R_(t) = 2.2 dd, J = 14.4 and 7.4 Hz); 2.05 (8 H, br s); 2.12 (2 H, s); 2.14-2.27 (2 Alkylation/ min. H, m); 2.93-3.03 (1 H, m); 3.18-3.26 (4 H, m); 4.40 (2 H, t, J = 6.1 57% Hz); 4.80 (2 H, dd, J = 7.8 and 6.0 Hz); 7.26-7.33 (3 H, m); 7.36- 7.42 (2 H, m). ¹³C-NMR (CDCl₃): 30.1; 31.2; 32.9; 33.0; 35.7; 38.0; 40.2; 44.4; 58.0; 77.3; 126.9; 127.4; 127.8; 147.2; 173.7. 255 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.62-1.75 (2 H, m); 1.83 (2 H, Alkylation/ 357.4, R_(t) = 2.5 dd, J = 14.4 and 7.4 Hz); 1.91-2.04 (2 H, m); 2.05 (6 H, s); 2.17- 58% min. 2.33 (2 H, m); 2.35 (2 H, s); 2.88-2.96 (1 H, m); 2.98 (2 H, s); 3.15 (2 H, t, J = 7.1 Hz); 4.34 (2 H, t, J = 6.1 Hz); 4.76 (2 H, dd, J = 7.8 and 6.0 Hz); 7.25-7.32 (3 H, m); 7.36-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 31.2; 33.0; 33.1; 35.9; 38.0; 40.1; 43.4; 59.0; 77.2; 126.8; 127.6; 127.8; 173.7. 256 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.14-1.36 (6 H, m); 1.38-1.62 (6 H, m); 1.62-1.78 Step9/ 372.4, R_(t) = 2.6 (4 H, m); 1.91-1.97 (2 H, m); 1.98-2.22 (5 H, m); 2.26 (6 H, s); 2.28 Alkylation/ min. (2 H, s); 2.47-2.58 (2 H, m); 3.12 (2 H, s); 3.33-3.40 (2 H, m). 42% ¹³C-NMR (CDCl₃): 16.9; 25.1; 26.9; 28.5; 31.6; 32.1; 33.7; 34.9; 36.3; 37.9; 38.8; 42.0; 44.2; 57.5; 61.1; 124.0; 174.3. 257 3 Ex. no. 247/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.21-1.34 (6 H, m); 1.43-1.76 (14 H, m); 1.85- Reduction/ 363.4 (100%) 1.92 (4 H, m); 2.00-2.10 (3 H, m); 2.27 (6 H, s); 2.37-2.44 (4 H, m); 87% [MH − NHMe₂]⁺ = 2.57-2.64 (2 H, m); 3.12 (3 H, s). 318.4 (13%), ¹³C-NMR (CDCl₃): 12.5; 25.1; 27.4; 28.5; 31.6; 33.1; 35.1; 38.0; R_(t) = 1.9 min 41.5, 44.3; 49.2; 51.4; 54.8; 57.6; 69.5; 76.9, 77.2; 77.5; 78.6. 258 3 Ex. no. 424/ m/z: [MH − ¹H-NMR (CDCl₃): 1.20-1.34 (6 H, m); 1.35 (6 H, s); 1.39-1.67 (12 H, Reductive HNMe₂]⁺ = 301.3 m); 1.68-1.74 (2 H, m); 1.99-2.10 (1 H, m); 2.26 (6 H, s); 2.33 (2 H, amination/ (15%) s); 2.53-2.60 (4 H, m). 52% [M + H]⁺ = 346.4 ¹³C-NMR (CDCl₃): 25.1; 27.0; 27.3; 28.5; 31.2; 33.0; 35.0; 38.0; (100%), R_(t) = 0.3 39.4; 41.5; 44.3; 52.8; 54.5; 57.7; 69.4; 124.9. min. 259 3 Ex. no. 424/ m/z: [MH − ¹H-NMR (CDCl₃): 1.16-1.38 (6 H, m); 1.43-1.61 (4 H, m); 1.49 (3.6 Acylation/ HNMe₂]⁺ = 315.3 H, s); 1.50 (2.4 H, s); 1.63-1.77 (5.2 H, m); 1.83 (0.8 H, t, J = 7.1 26% (2%) Hz); 2.01-2.12 (1 H, m); 2.26 (6 H, s); 2.47 (1.2 H, s); 2.48 (0.8 H, [M + H]⁺ = 360.4 s); 3.17 (1.2 H, s); 3.24 (0.8 H, s); 3.49 (0.8 H, t, J = 7.1 Hz); 3.54 (100%), R_(t) = 2.7 (1.2 H, t, J = 7.2 Hz). min. ¹³C-NMR (CDCl₃): 25.09; 25.12; 27.00; 27.03; 28.48; 28.51; 29.8; 30.36; 30.43; 32.0; 33.5; 37.8; 40.6; 42.8; 43.6; 43.9; 44.1; 44.2; 44.6; 45.9; 57.77; 57.84; 58.8; 60.5; 124.7; 124.8; 166.7; 166.8. 260 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.34-1.43 (2 H, m); 1.58-1.67 (1 H, m); 1.70-1.79 Step3/ 357.3, R_(t) = 2.2 (2 H, m); 1.95-2.02 (3 H, m); 2.04 (6 H, s); 2.14 (2 H, s); 2.15-2.30 Alkylation/ min. (2 H, m); 2.47-2.57 (1 H, m); 3.23 (1 H, dd, J = 13.7 and 7.5 Hz); 45% 3.28 (2 H, s); 3.36 (1 H, dd, J = 13.6 and 7.6 Hz); 3.47 (1 H, dd, J = 8.6 and 6.3 Hz); 3.73-3.80 (1 H, m); 3.82-3.91 (2 H, m); 7.26-7.32 (3 H, m); 7.36-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 30.2; 32.7; 32.8; 35.9; 38.0; 44.2; 45.3; 58.6; 60.1; 71.4; 126.8; 127.4; 127.8; 174.0. 261 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.58-1.62 (1 H, m); 1.67-1.76 Alkylation/ 357.3, R_(t) = 2.5 (2 H, m); 1.85-2.03 (3 H, m); 2.05 (6 H, s); 2.15-2.35 (2 H, m); 2.37 42% min. (2 H, s); 2.40-2.49 (1 H, m); 3.01 (2 H, s); 3.17 (1 H, dd, J = 13.7 and 7.6 Hz); 3.30 (1 H, dd, J = 13.7 and 7.6 Hz); 3.41 (1 H, dd, J = 8.6 and 6.3 Hz); 3.68-3.88 (3 H, m); 7.26-7.32 (3 H, m); 7.36-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 31.1; 32.9; 33.0; 36.1; 37.9; 38.0; 43.3; 45.2; 59.6; 60.7; 67.7; 71.3; 126.8, 127.6; 127.8; 136.1; 174.0. 262 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.44-1.58 (1 H, m); 1.64-1.93 Step3/ 371.3, R_(t) = 2.5 (7 H, m); 1.95-2.03 (2 H, m); 2.04 (6 H, br s); 2.12 (2 H, s); 2.13- Alkylation/ min. 2.30 (2 H, m); 3.24-3.42 (4 H, m); 3.67-3.74 (1 H, m); 3.76-3.89 (2 58% H, m); 7.26-7.33 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 25.6; 30.1; 31.4; 32.9; 33.3; 35.7; 38.0; 40.0; 44.6; 58.3; 67.7; 77.02; 126.8; 127.5; 128.0; 173.6. 263 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.31-1.49 (3 H, m); 1.58-1.76 (4 H, m); 1.78-1.89 Alkylation/ 371.4, R_(t) = 2.7 (2 H, m); 1.90-2.03 (3 H, m); 2.04 (6 H, s); 2.15-2.33 (2 H, m); 2.35 57% min. (2 H, s); 2.99-3.06 (2 H, m); 3.23-3.38 (2 H, m); 3.63-3.84 (3 H, m); 7.27-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 25.6; 30.0; 30.01; 31.3; 33.0; 33.2; 35.8; 38.0; 39.8; 43.6; 59.2; 60.6; 67.6; 76.9; 126.7; 127.5; 127.7; 173.6. 264 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.33-1.42 (2 H, m); 1.47-1.67 (4 H, m); 1.69-1.77 Step3/ 371.4, R_(t) = 2.4 (2 H, m); 1.90-2.01 (3 H, m); 2.03 (6 H, s); 2.05-2.21 (4 H, m); 3.23 Alkylation/ min. (2 H, s); 3.28 (2 H, t, J = 7.4 Hz); 3.35 (1 H, dd; J = 8.2 and 6.9 Hz); 50% 3.70-3.77 (1 H, m); 3.81-3.93 (2 H, m); 7.26-7.32 (3 H, m); 7.35- 7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.2; 30.7; 32.2; 32.8; 35.7; 36.9; 38.0; 41.4; 44.4; 57.9; 60.1; 67.8; 73.1; 126.8; 127.4; 127.7; 173.6. 265 3 Ex. no. 424/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.18-1.36 (10 H, m); 1.38-1.74 (15 H, m); 2.04 (1 Reductive 349.4, R_(t) = 0.6 H, m); 2.12-2.36 (2 H, m); 2.26 (6 H, s); 2.53 (2 H, br s); 3.35 (2 H, amination/ min. dt, J = 1.8 and 12.1 Hz); 3.94 (2 H, dd, J = 3.7 and 10.9 Hz). 68% ¹³C-NMR (CDCl₃): 25.0; 27.2; 28.4; 31.7; 33.0; 34.3; 34.8; 38.0; 41.6; 44.2; 55.0; 57.8; 63.2; 68.0; 69.2. 266 3 Ex. no. 424/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.91 (6 H, d, J = 6.5 Hz); 1.16-1.40 (6 H, m); Reductive 321.4, R_(t) = 1.9 1.40-1.78 (13 H, m); 1.81 (2 H, t, J = 7.1 Hz); 2.05 (1 H, m); 2.28 (6 amination/ min. H, s); 2.60-2.76 (4 H, m); 2.96 (2 H, br s). 30% ¹³C-NMR (CDCl₃): 22.3; 25.1; 26.3; 27.2; 28.4; 31.9; 33.7; 35.6; 37.8; 41.7; 44.0; 54.0; 55.1; 67.3. 267 3 Ex. no. 424/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.81 (2 H, dd, J = 5.0 and 7.1 Hz); 1.20 (2 H, Reductive 344.4, R_(t) = 0.6 partially overlapped dd, J = 4.9 and 7.1 Hz); 1.16-1.36 (6 H, m); amination/ min. 1.38-1.74 (14 H, m); 2.04 (1 H, m); 2.26 (6 H, s); 2.33 (2 H, s); 74% 2.54-2.67 (4 H, m). ¹³C-NMR (CDCl₃): 8.1; 13.9; 25.0; 27.3; 28.4; 32.9; 34.1; 34.9; 38.0; 41.4; 44.3; 54.4; 57.7; 69.3; 123.4. 268 3 Ex. no. 424/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.57-1.36 (6 H, m); 1.38-1.75 (12 H, m); 1.87- Reductive 358.4, R_(t) = 1.3 1.95 (2 H, m); 1.97-2.21 (5 H, m); 2.26 (6 H, s); 2.34 (2 H, s); 2.45- amination/ min. 2.54 (4 H, m); 2.58 (2 H, t, J = 6.8 Hz). 83% ¹³C-NMR (CDCl₃): 17.0; 25.0; 27.3; 28.4; 32.2; 33.0; 34.6; 35.0; 36.6; 37.9; 41.4; 44.3; 52.5; 54.6; 57.7; 69.4; 124.5. 269 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.25-1.45 (4 H, m); 1.50-1.58 (2 H, m); 1.70-1.80 Step3/ 371.4, R_(t) = 2.4 (2 H, m); 1.80-1.93 (1 H, m); 2.00 (8 H, s); 2.14 (2 H, s); 2.15-2.22 Alkylation/ min. (2 H, m); 3.14 (2 H, d, J = 7.3 Hz); 3.26 (2 H, s); 3.35 (2 H, dt, J = 44% 11.7 and 2.1 Hz); 3.94-3.99 (2 H, m); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.1; 30.7; 32.8; 33.7; 35.9; 37.9; 44.3; 48.4; 59.2; 60.0; 67.5; 126.8; 127.4; 127.8; 174.1. 270 1 Ex. no. 431 / m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.23-1.40 (4 H, m); 1.45-1.52 (2 H, m); 1.68-1.84 Alkylation/ 371.3, R_(t) = 2.6 (3 H, m); 1.90-2.02 (2 H, m); 2.05 (6 H, s); 2.18-2.35 (2 H, m); 2.38 35% min. (2 H, s); 3.01 (2 H, s); 3.09 (2 H, d, J = 7.3 Hz); 3.30 (2 H, dt, J = 11.7 and 2.2 Hz); 3.90-3.96 (2 H, m); 7.26-7.32 (3 H, m); 7.36-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 30.7; 33.1; 33.7; 36.1; 38.0; 43.4; 48.3; 60.2; 67.5; 126.8; 127.6; 127.8; 174.1. 271 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.30-1.40 (2 H, m); 1.41-1.59 (3 H, m); 1.67-1.76 Alkylation/ 371.4, R_(t) = 2.6 (2 H, m); 1.90-2.01 (2 H, m); 2.04 (6 H, s); 2.05-2.15 (2 H, m); 40% min. 2.16-2.33 (2 H, m); 2.36 (2 H, s); 2.98 (2 H, s); 3.23 (2 H, t, J = 7.4 Hz); 3.30 (1 H, dd; J = 8.2 and 6.9 Hz); 3.68-3.75 (1 H, m); 3.78- 3.90 (2 H, m); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.0; 30.6; 32.2; 33.1; 35.9; 36.9; 38.0; 41.3; 43.5; 58.9; 60.7; 67.8; 73.1; 126.7; 127.6; 127.8; 173.6. 272 1 273 3 Ex. no. 424/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.89 (6 H, d, J = 6.5 Hz); 1.18-1.36 (6 H, m); Reductive 307.4, R_(t) = 0.6 1.38-1.80 (13 H, m); 2.64 (1 H, m); 2.13 (2 H, d, J = 7.3 Hz); 2.25 (2 amination/ min. H, s); 2.27 (6 H, s); 2.51 (2 H, t, J = 6.5 Hz). 62% ¹³C-NMR (CDCl₃): 21.0; 25.1; 27.2; 27.4; 28.4; 33.1; 34.7; 38.0; 41.5; 44.4; 54.8; 57.8; 65.3; 69.1. 274 2 Ex. no. 234 [M + H]⁺ m/z = ¹H-NMR (CDCl₃): 1.14-1.36 (6 H, m); 1.38-1.60 (6 H, m); 1.60-1.78 Step9/ 333.4, R_(t) = 2.6 (6 H, m); 1.80-1.94 (2 H, m); 1.96-2.10 (3 H, m); 2.25 (8 H, s); 2.51 Alkylation/ min. (1 H, m); 3.03 (2 H, s); 7.57 (2 H, d, J = 7.6 Hz). 90% ¹³C-NMR (CDCl₃): 18.4; 25.1; 26.4; 26.9; 28.5; 31.5; 33.8; 36.5; 37.9; 42.0; 44.0; 47.6; 57.7; 61.2; 173.8. 276 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.19 (2 H, td, J = 4.6 and 5.8 Hz); 0.49 (2 H, m); Step9/ 319.4, R_(t) = 2.4 8.58 (1 H, m); 1.16-1.37 (6 H, m); 1.38-1.62 (6 H, m); 1.64-1.79 (4 Alkylation/ min. H, m); 2.06 (1 H, m); 2.27 (6 H, s); 2.28 (2 H, s); 3.11 (2 H, d, J = 7.1 50% Hz); 3.19 (2H, s). ¹³C-NMR (CDCl₃): 3.3; 9.0; 25.1; 26.8; 28.5; 31.8; 36.3, 37.9; 42.3; 44.2; 46.8; 57.7; 60.9; 173.6. 277 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.84-1.02 (2 H, m); 1.06-1.36 (10 H, m); 1.38- Step9/ 361.4, R_(t) = 3.0 1.84 (15 H, m); 2.04 (1 H, m); 2.26 (6 H, s); 2.28 (2 H, s); 3.06 (2 H, Alkylation/ min. d, J = 7.9 Hz), 3.07 (2 H, s). 51% ¹³C-NMR (CDCl₃): 25.1; 25.7; 26.3; 26.9; 28.5; 30.1; 30.8; 31.8; 35.9; 36.4; 37.9; 42.3; 44.2; 48.6; 57.7; 61.6; 174.3. 278 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.10-1.36 (8 H, m); 1.38-180 (16 H, m); 1.98- Step9/ 347.4, R_(t) = 2.8 2.18 (2 H, m); 2.26 (6 H, s); 2.28 (2 H, s); 3.09 (2 H, s); 3.17 (2 H, d, Alkylation/ min. J = 7.9 Hz). 61% ¹³C-NMR (CDCl₃): 25.07; 25.14; 26.9; 28.5; 30.3; 31.7; 36.3; 37.9; 38.0; 42.2; 44.2; 47.2; 57.7; 61.1; 174.0. 279 2 Ex. no. 24b/ m/z: [M + H]⁺ = Optical rotation□□□□□□□□□ = +4.74°, (c = 1.0, MeOH) Alkylation/ 363.3, R_(t) = 2.2 ¹H-NMR (CDCl₃): 1.41-1.50 (2 H, m); 1.57-1.67 (1 H, m); 1.72-1.82 58% min. (2 H, m); 1.94-2.07 (5 H, m); 2.10 (6 H, s); 2.19 (2 H, s); 2.45-2.57 According to (1 H, m); 3.18-3.26 (3 H, m); 3.35 (1 H, dd, J = 13.6 and 7.6 Hz); HPLC on 3.46 (1 H, dd, J = 8.6 and 6.3 Hz); 3.72-3.79 (1 H, m); 3.81-3.91 (2 Chiracel OD H, m); 6.82-6.86 (1 H, m); 7.04 (1 H, dd, J = 5.0 and 3.6 Hz); 7.22- [(cyclohexane/ 7.26 (1 H, m). 2 PrOH/Et2NH ¹³C-NMR (CDCl₃): 30.1; 32.6; 32.7; 35.8; 38.0; 38.02; 44.0; 45.3; (70:30:0.1)] the 58.7; 59.2; 67.7; 71.4; 123.4; 124.8; 126.3; 173.9. enantiomer excess is > 98%. 280 2 Ex. no. 24b/ m/z: [M + H]⁺ = Optical rotation□□□□□□□□□□□ −3.28°, (c = 1.0, MeOH) Alkylation/ 363.3, R_(t) = 2.2 60% min ¹H-NMR (CDCl₃): 1.42-1.50 (2 H, m); 1.57-1.67 (1 H, m); 1.73-1.83 According to (2 H, m); 1.94-2.08 (5 H, m); 2.10 (6 H, s); 2.19 (2 H, s); 2.46-2.56 HPLC on (1 H, m); 3.19-3.27 (3 H, m); 3.35 (1 H, dd, J = 13.6 and 7.6 Hz); Chiracel OD 3.46 (1 H, dd, J = 8.6 and 6.3 Hz); 3.72-3.79 (1 H, m); 3.82-3.92 (2 [(cyclohexane/ H, m); 6.83-6.88 (1 H, m); 7.03-7.07 (1 H, m); 7.22-7.27 (1 H, m). 2 PrOH/Et2NH ¹³C-NMR (CDCl₃): 30.1; 32.6; 32.7; 35.8; 37.9; 38.0; 44.0; 45.3; (70:30:0.1)] the 58.8; 59.2; 67.7; 71.4; 123.5; 124.8; 126.3; 173.9. enantiomer excess is 91%. 281 2 Ex. no. 347 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.3 Hz); 1.16-1.36 (8 H, m); 1.40- Step9/ 321.4, R_(t) = 2.6 1.80 (12 H, m); 2.04 (1 H, m); 2.26 (6 H, s); 2.27 (2 H, s); 3.06 (2 H, Alkylation/ min. s); 3.23 (2 H, t, J = 7.3 Hz). 65% ¹³C-NMR (CDCl₃): 13.6; 19.9; 25.1; 26.9; 28.5; 29.2; 31.5; 31.6; 36.2; 41.8; 42.2; 44.2; 57.7; 60.7; 173.9. 282 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.12-1.34 (6 H, m); 1.38-1.60 (6 H, m); 1.61-1.78 Step9/ 279.3, R_(t) = 1.4 (4 H, m); 2.04 (1 H, s); 2.25 (8 H, s); 2.80 (3 H, s); 3.07 (2 H, s). Alkylation/ min. ¹³C-NMR (CDCl₃): 25.0; 26.9; 28.3; 29.5; 31.9; 36.0; 37.9; 42.0; 78% 44.0; 57.6; 63.3; 174.0. 283 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.23-1.32 (2 H, m); 1.44 (2 H, t, J = 6.9 Hz); 1.61- Reductive 343.3, R_(t) = 0.3 1.69 (2 H, m); 1.81-1.89 (4 H, m); 1.98-2.02 (1 H, m); 2.03 (6 H, s); amination/ min. 2.18-2.33 (3 H, m); 2.43 (2 H, s); 2.47 (2 H, t, J = 6.9 Hz); 2.97-3.07 9% (1 H, m); 4.41 (2 H, t, J = 6.2 Hz); 4.78 (2 H, dd, J = 7.9 and 5.9 Hz); 7.27-7.33 (3 H, m); 7.34-7.39 (2 H, m). ¹³C-NMR (CDCl₃): 31.1; 32.8; 34.0; 37.9; 37.93; 38.1; 41.2; 53.9; 54.3; 60.5; 65.7; 77.8; 126.4; 127.6; 127.7. 284 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.23-1.31 (2 H, m); 1.40-1.46 (2 H, m); 1.56-1.70 Reductive 343.3, R_(t) = 0.7 (3 H, m); 1.80-1.95 (2 H, m); 1.97-2.02 (1 H, m); 2.04 (6 H, s); amination/ min. 2.17-2.33 (2 H, m); 2.34-2.42 (3 H, m); 2.42-2.54 (4 H, m); 3.47- 10% 3.52 (1 H, m); 3.70-3.77 (1 H, m); 3.80-3.90 (2 H, m); 7.24-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 31.0; 31.02; 34.5; 37.9; 38.0; 38.7; 41.2; 53.9; 59.8; 65.6; 67.7; 72.4; 126.5; 127.6; 127.7. 285 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.38 (2 H, dd, J = 6.3 and 5.1 Hz); 0.73 (2 H, dd, Alkylation/ 343.4, R_(t) = 0.5 J = 6.3 and 5.1 Hz); 1.24-1.33 (2 H, m); 1.44-1.51 (2 H, m); 1.63- 2Steps 6% min. 1.72 (4 H, m); 1.87-2.00 (2 H, m); 2.05 (6 H, s); 2.15-2.28 (2 H, m); 2.55-2.67 (4 H, m); 2.78-2.84 (2 H, m); 6.40-6.80 (1 H, br s); 7.26- 7.34 (3 H, m); 7.35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.7; 30.9; 34.3; 38.0; 41.2; 51.0; 53.4; 53.5; 55.6; 57.7; 65.4; 126.5; 127.6; 127.65. 286 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.16-1.34 (6 H, m); 1.38-1.86 (18 H, m); 2.04 (1 Step9/ 333.4, R_(t) = 2.6 H, m); 2.26 (6 H, s); 2.27 (2 H, s); 3.03 (2 H, s); 4.48 (1 H, m). Alkylation/ min. ¹³C-NMR (CDCl₃): 24.3; 25.1; 26.9; 28.5; 28.8; 31.3; 36.4; 37.9; 33% 42.5; 44.2; 51.9; 56.6; 57.6; 173.6. 287 2 Ex. no. 234 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.14-1.34 (6 H, m); 1.38-178 (12 H, m); 1.80- Step9/ 377.4, R_(t) = 2.7 1.94 (4 H, m); 1.98-2.16 (3 H, m); 2.25 (6 H, s); 2.26 (2 H, s); 3.10 Alkylation/ min. (2 H, s); 3.13 (3 H, s); 3.20-3.27 (2 H, m). 79% ¹³C-NMR (CDCl₃): 12.3; 25.0; 26.9; 28.3; 31.3; 31.6; 31.9; 36.3; 37.5; 37.9; 42.4; 44.2; 49.2; 57.5; 61.2; 78.1; 173.6. 288 2 Ex. no. 24b/ m/z: [MH − ¹H-NMR (CDCl₃): 1.37 (6 H, s); 1.44-1.53 (2 H, m); 1.80-1.88 (2 H, Alkylation/ HNMe₂]⁺ = 315.3 m); 1.95-2.15 (4 H, m); 2.10 (6 H, s); 2.23 (2 H, s); 3.39 (2 H, s); 14% (100%) 3.53 (2 H, s); 6.86 (1 H, dd, J = 3.6 and 1.0 Hz); 7.04 (1 H, dd, J = [M + H]⁺ = 380.3 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). (35%), R_(t) = 2.5 ¹³C-NMR (CDCl₃): 24.8; 32.4; 32.5; 33.0; 36.1; 38.0; 43.4; 51.2; min. 59.4; 59.7; 123.5; 124.6; 124.8; 128.3; 142.8; 175.2. 289 1 Ex. no. 24a/ m/z: [MH − ¹H-NMR (CDCl₃): 1.34 (6 H, s); 1.52 (2 H, ddd, J = 13.3, 9.4 and 4.0 Alkylation/ HNMe₂]⁺ = 315.2 Hz); 1.73-1.81 (2 H, m); 1.94-2.05 (2 H, m); 2.07-2.16 (2 H, m); 28% (100%) 2.10 (6 H, s); 2.36 (2 H, s); 3.35 (2 H, s); 3.37 (2 H, s); 6.84 (1 H, dd, [M + H]⁺ = 360.3 J = 3.6 and 1.0 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, (50%), R_(t) = 2.6 dd, J = 5.1 and 0.9 Hz). min. ¹³C-NMR (CDCl₃): 24.7; 32.6; 32.9; 36.1; 38.1; 43.0; 51.2; 59.6; 60.0; 123.6; 124.6; 125.1; 126.3; 142.3; 175.2. 290 2 Ex. no. 130/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.03-0.07 (2 H, m); 0.41-0.48 (2 H, m); 0.59-0.69 N-Demethyl- 333.3 and (1 H, m); 1.41 (2 H, dd, J = 14.4 and 7.0 Hz); 1.47-1.57 (2 H, m); ation/23% 302.2, R_(t) = 2.6 1.71-2.03 (6 H, m); 2.11 (3 H, s); 2.24 (2 H, s); 3.21 (2 H, s); 3.31- min. 3.36 (2 H, m); 6.87 (1 H, dd, J = 3.5 and 1.0 Hz); 6.95 (1 H, dd, J = 5.1 and 3.5 Hz); 7.21 (1 H, dd, J = 5.1 and 1.0 Hz). The replaceable proton was not identified. ¹³C-NMR (CDCl₃): 4.3; 8.6; 28.7; 32.4; 32.5; 33.7; 35.8; 42.6; 43.3; 56.3; 59.3; 123.6, 126.4; 173.4. 291 3 Ex. no. 424/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.10-1.38 (6 H, m); 1.40-1.88 (10 H, m); 2.04 (1 Acylation/ 335.4, R_(t) = 2.4 H, m); 2.25 (6 H, s); 2.91 (2 H, s); 3.22-3.27 (2 H, m); 3.53 (2 H, t, 37% min. J = 7.3 Hz); 3.90 (1 H, m); 4.75 (2 H, dd, J = 5.6 and 8.6 Hz); 4.89- 4.93 (2 H, m). ¹³C-NMR (CDCl₃): 25.08; 25.10; 26.8; 27.0; 28.5; 29.7; 31.6, 33.4; 37.7; 38.3; 38.4; 40.6; 42.6; 44.0; 44.2; 44.5; 44.6; 57.6; 57.7; 58.8; 59.6; 73.03; 73.07; 169.3; 169.4. 292 3 Ex. no. 424/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15 (6 H,s); 1.19-1.35 (6 H, m); 1.39-1.75 (14 H, Alkylation/ 351.4, R_(t) = 2.0 m); 2.04 (1 H, m); 2.26 (6 H, s); 2.31 (2 H, s); 2.36-2.43 (2 H, m); 60% min. 2.54 (2 H, t, J = 6.8 Hz); 3.17 (3 H, s). ¹³C-NMR (CDCl₃): 25.0; 25.2; 27.2; 28.5; 33.1; 35.0; 37.9; 38.0; 41.4; 44.2; 49.1; 52.0; 54.8; 57.7; 69.5; 73.9. 293 2 Ex. no. 234 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.17-1.35 (5 H, m); 1.40-1.78 (12 H, m); 1.93- Step9/ 349.4, R_(t) = 2.3 2.10 (2 H, m); 2.26 (6 H, s); 2.29 (2 H, s); 2.51 (1 H, td, J = 14.2 and Alkylation/ min. According 6.9 Hz); 3.10 (2 H, s); 3.20 (1 H, dd, J = 13.6 and 7.6 Hz); 3.35 (1 H, 60% to HPLC on dd, J = 13.6 and 7.6 Hz); 3.46 (1 H, dd, J = 8.6 and 6.2 Hz); 3.70- Chiracel OD 3.79 (1 H, m), 3.80-3.90 (2 H, m). [(cyclohexane/ ¹³C-NMR (CDCl₃): 25.0; 26.9; 28.5; 30.1, 31.62; 31.65; 36.6; 37.9; 2 PrOH/Et2NH 37.94; 42.1; 44.1; 45.2; 57.7; 61.5; 67.7; 71.4; 174.3. (90:10:0.1)] the Optical rotation:□□□□D□□□□□4.57°, (c = 1.13, MeOH). enantiomer excess is ≧ 97%. 294 2 Ex. no. 234 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.16-1.33 (6 H, m); 1.39-1.76 (11 H, m); 1.91- Step9/ 349.4, R_(t) = 2.3 2.09 (2 H, m); 2.25 (6 H, s); 2.27 (2 H, s); 2.49 (1 H, td, J = 14.1 and Alkylation/ min. 7.0 Hz); 3.09 (2 H, s); 3.18 (1 H, dd, J = 13.6 and 7.6 Hz); 3.33 (1 H, 44% According to dd, J = 13.6 and 7.6 Hz); 3.44 (1 H, dd, J = 8.6 and 6.3 Hz); 3.73 (1 HPLC on H, dd, J = 15.4 and 7.6 Hz); 3.78-3.88 (2 H, m). Chiracel OD ¹³C-NMR (CDCl₃): 25.0; 26.8; 28.4; 30.1; 31.57; 31.59; 36.5; 37.8; [(cyclohexane/ 37.9; 42.0; 44.1; 45.1; 57.8; 61.4, 67.6; 71.3; 174.2. 2 PrOH/Et2NH LC-MS (Method 1): m/z: [M + H]⁺ = 349.4, R_(t) = 2.3 min. (90:10:0.1)] the Optical rotation: □□□□D□□□□□□□6.24°, (c = 1.0, MeOH). enantiomer excess = 93%. 295 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.33-1.42 (2 H, m); 1.50 (2 H, t, J = 6.9 Hz); 1.64- Reductive 349.3, R_(t) = 0.3 1.73 (2 H, m); 1.86 (2 H, dd, J = 15.0 and 7.6 Hz); 1.89-1.97 (2 H, amination/ min. m); 2.04-2.10 (2 H, m); 2.10 (6 H, s); 2.26-2.34 (2 H, m); 2.41 (2 H, 10% s); 2.50 (2 H, t, J = 6.8 Hz); 2.96 (1 H, m); 4.41 (2 H, t, J = 6.2 Hz); 4.78 (2 H, dd, J = 7.9 and 6.0 Hz); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.23 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 32.9; 33.7; 34.0; 34.4; 38.1; 40.9; 53.9; 54.3; 59.7; 65.7; 77.8; 123.2; 124.9; 126.2. 296 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.76 (8 H, m); 1.85-2.06 (4 H, m); 2.13 (6 H, Reductive 349.3, R_(t) = 0.4 s); 2.34-2.57 (7 H, m); 3.47-3.52 (1 H, m); 3.69-3.77 (1 H, m); amination/ min. 3.80-3.90 (2 H, m); 6.87(1 H, dd, J = 3.1 Hz); 7.04 (1 H, dd, J = 5.1 12% and 3.5 Hz); 7.24 (1 H, br d, J = 5.2 Hz). ¹³C-NMR (CDCl₃): 31.0; 33.6; 34.2; 38.1; 38.6; 41.0; 53.9; 59.8; 67.8; 72.4; 123.4; 125.2; 126.2. 297 3 Ex. no. 424/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.08-1.38 (6 H, m); 1.40 and 1.41 (6 H, 2 s); Acylation/ 351.4, R_(t) = 2.8 1.42-1.82 (12 H, m); 2.08 (1 H, m); 2.26 (6 H, m); 3.17 (2 H, s); 3.18 70% min. (1 H, s); 3.28 (0.5 H, s); 3.48 (1.5 H, s); 3.54 (1.6 H, t, J = 7.4 Hz); 3.74 (0.4 H, t, J = 7.0 Hz). ¹³C-NMR (CDCl₃): 24.1; 25.0; 26.9; 27.0; 28.4; 29.4; 30.0; 30.6; 30.9; 34.4; 37.7; 39.1; 42.8; 44.1; 45.8; 46.3; 51.5; 51.7; 57.8; 57.9; 60.3; 60.9; 79.6; 79.8; 172.5. 298 3 Ex. no. 297/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15 (6 H, s); 1.20-1.35 (6 H, m); 1.39-1.72 (12 H, Reduction/ 337.4, R_(t) = 1.3 m); 2.04 (1 H, m); 2.26 (6 H, s); 2.39 (2 H, s) 2.41 (2 H, s); 2.65 (2 84% min. H, t, J = 6.9 Hz); 3.20 (3 H, s). ¹³C-NMR (CDCl₃): 23.7; 25.2; 27.3; 28.4; 32.6; 34.9; 37.9; 41.7; 44.4; 49.3; 56.0; 57.9; 64.5; 71.1; 75.9. 299 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.16 (6 H, s); 1.39 (2 H, ddd, J = 13.3 and 10.2 Alkylation/ 385.3, R_(t) = 1.9 and 3.4 Hz); 1.52 (2 H, t, J = 6.7 Hz); 1.65-1.74 (4 H, m); 1.85-1.96 2Steps 82% min. (2 H, m); 2.10 (6 H, s); 2.11-2.18 (2 H, m); 2.41-2.49 (4 H, m); 2.50-2.57 (2 H, m); 3.18 (3 H, s); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 25.3; 33.7; 34.4; 38.0; 38.1; 40.9; 49.1; 52.0; 54.1; 59.6; 65.8; 73.9; 123.2; 124.9; 126.1. 300 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.16 (6 H, s); 1.24-1.33 (2 H, m); 1.47 (2 H, t, J = Alkylation/ 359.4, R_(t) = 2.0 6.6 Hz); 1.63-1.74 (4 H, m); 1.80-1.93 (2 H, m); 2.03 (6 H, s); 2.19- 2Steps 60% min. 2.33 (2 H, m); 2.43-2.58 (6 H, m); 3.19 (3 H, s); 7.23-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 25.3; 31.1; 34.6; 37.9; 38.0; 38.1; 41.2; 49.1; 52.1; 54.0; 60.5; 65.7; 73.9; 126.4; 127.6; 127.7. 301 3 Ex. no. 291/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.71 (3 H, d, J = 6.8 Hz); 1.12-1.32 (6 H, m); Reduction/ 323.4, R_(t) = 0.4 1.36-1.74 (12 H; m); 1.96-2.12 (2 H, m); 2.22 (1 H, d, J = 9.3 Hz); 25% min. 2.24 (6 H, s); 2.32 (1 H, td, J = 2.8 and 11.9 Hz); 2.46-2.54 (2 H, m); 2.64 (1 H, t, J = 11.8 Hz); 2.69-2.77 (1 H, m); 3.47 (1 H, t, J = 10.3 Hz); 3.66 (1 H, ddd, J = 2.6, 3.7 and 10.4 Hz); 6.53 (1 H, br s). ¹³C-NMR (CDCl₃): 15.0; 25.0; 27.15; 27.20; 28.5; 32.3; 32.5; 32.6; 34.7; 37.8; 41.5; 44.3; 54.4; 57.6; 64.8; 69.5; 71.7. 302 3 Ex. no. 291/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15-1.34 (6 H, m); 1.38-1.74 (12 H, m); 2.04 (1 Reduction/ 321.4, R_(t) = 0.3 H, m); 2.23 (2 H, s); 2.26 (6 H, s); 2.49 (2 H, t, J = 6.8 Hz); 2.69 (2 20% min. H, d, J = 7.2 Hz); 3.18 (1 H, m); 4.41 (2 H, t, J = 6.2 Hz); 4.76 (2 H, dd, J = 6.0 and 7.9 Hz). ¹³C-NMR (CDCl₃): 25.0; 27.3; 28.4; 33.1; 34.9; 35.0; 37.9; 41.6; 44.3; 54.6; 57.6; 59.9; 69.4; 76.6. 303 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.21-1.34 (4 H, m); 1.43 (2 H, t, J = 6.7 Hz); 1.62- Reductive 357.3, R_(t) = 1.3 1.73 (5 H, m); 1.80-2.00 (2 H, m); 2.05 (6 H, s); 2.23-2.37 (4 H, m); amination/ min. 2.41-2.56 (4 H, m); 3.37 (2 H, dt, J = 12.0 and 1.9 Hz); 3.96 (2 H, 51% dd, J = 10.8 and 3.5 Hz); 7.25-7.33 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 31.1; 31.8; 34.4; 34.5; 38.0; 41.3; 54.2; 63.1; 65.2; 68.0; 126.6; 127.6; 127.8. 304 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.20-1.42 (4 H, m); 1.50 (2 H, t, J = 6.5 Hz); 1.63- Reductive 363.4, R_(t) = 0.6 1.73 (5 H, m); 1.85-1.97 (2 H, m); 2.11 (6 H, s); 2.12-2.18 (2 H, m); amination/ min. 2.27 (2 H, d, J = 6.3 Hz); 2.40 (2 H, s); 2.45-2.54 (2 H, m); 3.37 (2 70% H, dt, J = 12.1 and 1.9 Hz); 3.95 (2 H, dd, J = 10.7 and 3.4 Hz); 6.85 (1 H, d, J = 3.4 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.23 (1 H, dd, J = 5.1 and 0.7 Hz). ¹³C-NMR (CDCl₃): 31.8; 33.8; 34.3; 34.4; 37.8; 38.1; 41.0; 54.3; 60.0; 63.1; 65.4; 68.0; 123.3; 125.0; 126.2. 305 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.25-1.53 (2H, m); 1.43-1.53 (3 H, m); 1.65-1.80 Reductive 357.4, R_(t) = 1.9 (4 H, m); 1.82-1.93 (4 H, m); 1.95-2.02 (1 H, m); 2.04 (6 H, s); amination/ min. 2.13-2.32 (2 H, m); 2.50-2.65 (6 H, m); 3.67-3.74 (1 H, m); 3.80- 36% 3.89 (2 H, m); 7.23-7.33 (3 H, m); 7.34-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 25.6; 30.9; 31.5; 34.3; 34.5; 38.0; 41.2; 53.7; 54.0; 60.7; 65.4; 67.6; 77.6; 126.6; 127.6; 127.7. 306 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.35-1.59 (5 H, m); 1.65-2.05 (9 H, m); 2.10 (6 H, Reductive 363.3, R_(t) = 1.3 s); 2.05-2.15 (2 H, m); 2.48-2.65 (6 H, m); 3.67-3.74 (1 H, m); amination/ min. 3.79-3.89 (2 H, m); 6.84 (1 H, dd, J = 3.5 and 1.0 Hz); 7.03 (1 H, 34% dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 25.6; 31.5; 33.6; 34.2; 34.5; 37.6; 38.1; 41.0; 53.8; 54.0; 59.6; 65.6; 67.6; 77.6; 123.3; 124.9; 126.2. 307 1 Ex. no. 129/ m/z: [MH − ¹H-NMR (CDCl₃): 1.33 (1 H, br s); 1.47-1.68 (6 H, m); 1.70-1.92 (6 N-Demethyl- HNMe]+ = H, m); 1.93-2.09 (4 H, m); 2.11 (3 H, s); 2.23 (1 H, td, J = 15.4, 7.8 ation/18% 316.3, R_(t) = 3.1 Hz); 2.29 (2 H, s); 3.10 (2 H, s); 3.11-3.18 (2 H, m); 6.88 (1 H, dd, min. J = 3.5 and 1.1 Hz); 6.96 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 18.5; 28.2; 28.7; 32.7; 33.6; 33.8; 34.2; 35.7; 38.1; 40.5; 44.6; 56.3; 57.7, 123.7; 126.3; 173.3. 308 2 Ex. no. 128/ ¹H-NMR (CDCl₃): 1.37 (1 H, s); 1.47-1.69 (6 H, m); 1.69-2.11 (10 N-Demethyl- H, m); 2.12 (3 H, s); 2.22-2.25 (2 H, m); 2.21-2.30 (1 H, m); 3.15- ation/35% 3.20 (4 H, m); 6.86-6.90 (1 H, m); 6.96 (1 H, dd, J = 5.0 and 3.6 Hz); 7.22 (1 H, dd, J = 5.0 and 0.6 Hz). ¹³C-NMR (CDCl₃): 18.5; 28.2; 28.7; 32.5; 336.; 33.7; 34.3; 35.7; 40.5; 43.3; 56.3; 58.9; 132.6; 126.4; 173.3. 309 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.38 (2 H, ddd, J = 13.2 and 10.0 and 3.4 Hz); Reductive 363.3, R_(t) = 0.6 1.46-1.62 (5 H, m); 1.65-1.74 (2 H, m); 1.84-1.98 (2 H, m); 1.99- amination/ min. 2.08 (2 H, m); 2.10 (6 H, s); 2.11-2.27 (2 H, m); 2.33-2.47 (4 H, m); 63% 2.52 (2 H, t, J = 6.6 Hz); 3.30-3.36 (1 H, m); 3.74 (1 H, dd, J = 15.8 and 7.5 Hz); 3.83 (1 H, dt, J = 8.2 and 4.7 Hz); 3.91 (1 H, dd, J = 8.1 and 7.4 Hz); 6.85 (1 H, dd, J = 3.5 and 0.9 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.1 and 0.6 Hz). ¹³C-NMR (CDCl₃): 32.3; 32.5; 33.7; 34.3; 37.8; 38.1; 40.9; 53.9; 55.8; 59.6; 65.6; 67.8; 73.4; 77.2; 123.2; 125.0; 126.2; 143.1. 310 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.33 (6 H, s); 1.37-1.47 (2 H, m); 1.69-1.79 (2 H, Alkylation/ 354.3, R_(t) = 2.6 m); 1.85-2.02 (2 H, m); 2.03 (6 H, s); 2.18-2.30 (2 H, m); 2.39 (2 H, 58% min. s); 3.31 (2 H, s); 3.34 (2 H, s); 7.24-7.31 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 24.7; 30.1; 32.78; 32.84; 36.2; 38.0; 42.9; 51.0; 60.3; 124.5; 126.6; 127.5; 127.8; 175.3. 311 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.42-1.49 (2 H, m); 1.64-1.81 (4 H, m); 1.86-1.92 Alkylation/ 377.3 (100%) (2 H, m); 1.94-2.05 (4 H, m); 2.06-2.14 (2 H, m, overlapped); 2.10 43% [MH − NHMe₂]⁺ = (6 H, s); 2.18 (2 H, s); 3.19 (3 H, s); 3.34 (2 H, s); 3.50 (2 H, s); 6.84 332.3 (99%), (1 H, dd, J = 3.5 and 0.8 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); R_(t) = 2.5 min. 7.24 (1 H, dd, J = 5.1 and 0.7 Hz). ¹³C-NMR (CDCl₃): 12.2; 29.6; 32.6; 32.8; 35.8; 38.1; 43.9; 45.0; 49.6; 59.4; 79.8; 123.4; 124.9; 126.3, 174.6. 312 1 Ex. no. 431/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.39 (2 H, m); 1.66-1.78 (4 H, m); 1.82-1.88 Alkylation/ 371.3 (47%) (2 H, m); 1.90-1.99 (2 H, m); 2.01-2.09 (2 H, m, overlapped); 2.03 55% [MH − NHMe₂]⁺ = (6 H, s); 2.11-2.33 (2 H, m); 2.36 (2 H, s); 3.11 (5 H, s); 3.44 (2 H, 326.3 (100%), s); 7.28-7.31 (3 H, m); 7.36-7.40 (2 H, m). R_(t) = 2.9 min. ¹³C-NMR (CDCl₃): 12.2; 29.5; 30.1; 32.9; 36.2; 38.1; 44.9; 49.5; 60.2; 79.7; 126.6; 127.6; 127.7, 174.6. 313 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.19 (3 H, t, J = 7.0 Hz); 1.42-1.51 (2 H, m); 1.73- Alkylation/ 351.3, R_(t) = 2.3 1.82 (2 H, m); 1.93-2.07 (4 H, m); 2.11 (6 H, s); 2.18 (2 H, s); 3.35 79% min. (2 H, s); 3.44 (2 H, t, J = 5.3 H); 3.48 (2 H, q, J = 7.0 Hz); 3.52-3.57 (2 H, m); 6.85 (1 H, dd, J = 3.5 and 1.1 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 15.2; 32.6; 32.7; 35.8; 38.1; 42.4; 44.2; 59.3; 66.2; 68.5; 123.4; 124.9; 126.2; 173.8. 314 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.25 (2 H, s); 1.32 (6 H, s); 1.36-1.46 (2 H, m); Acylation/ 379.3, R_(t) = 2.8 1.58-1.74 (4 H, m); 1.84-2.06 (1.5 H, m); 2.09 (2.5 H, s); 2.11 (3.5 47% min. H, s); 2.14-2.24 (0.5 H, m); 2.45 (0.7 H, s); 2.46 (1.3 H, s); 3.21 (1.4 H, s); 3.22 (1.6 H, s); 3.36 (0.8 H, s); 3.40 (1.2 H, s); 3.47 (1.2 H, t, J = 7.3 Hz); 3.53 (0.8 H, t, J = 7.2 Hz); 6.83 (1 H, m); 7.04 (1 H, m); 7.24 (1 H, m). ¹³C-NMR (CDCl₃): 19.1; 24.6; 24.8; 29.7; 31.0; 32.8; 33.2; 35.7; 37.0; 38.08; 38.10; 40.0; 42.0; 43.9; 45.0; 45.5; 45.8; 49.2; 49.3; 53.4; 55.6; 57.0; 59.7; 59.8; 74.9; 75.0; 123.3; 123.4; 124.8; 125.0; 126.1; 126.3; 143.7; 169.3; 169.4. 315 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.46 (2 H, m); 1.56-1.74 (4 H, m); 1.84-2.22 Acylation/ 351.3, R_(t) = 2.6 (4 H, m); 2.09 (3.5 H, s); 2.11 (2.5 H, s); 2.51 (2 H, t, J = 6.4 Hz); 48% min. 3.34 (1.2 H, s); 3.35 (3 H, s); 3.37 (0.8 H, s); 3.47 (2 H, dd, J = 6.8 and 13.8 Hz); 3.60-3.73 (2 H, m); 6.83-6.86 (1 H, m); 7.01-7.06 (1 H, m); 7.21-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 31.0; 31.2; 32.9; 33.3; 34.6; 35.0; 35.4; 36.9; 38.1; 40.0; 42.0; 43.9; 45.1; 56.6; 58.8; 58.9; 59.9; 68.5; 123.2; 123.5; 124.9; 125.0; 126.0; 126.3; 169.6; 169.7. 316 1 Ex. no. 131/ m/z: [MH − ¹H-NMR (CDCl₃): 0.00-0.05 (2 H, m); 0.40-0.45 (2 H, m); 0.55-0.66 N-Demethyl- HNMe]+ = (1 H, m); 1.38 (2 H, dd, J = 14.4 and 7.0 Hz); 1.43-1.57 (3 H, m); ation/12% 302.3, R_(t) = 2.8 1.69-1.81 (2 H, m); 1.82-2.04 (4 H, m); 2.11 (3 H, s); 2.30 (2 H, s); min. 3.13 (2 H, s); 3.28-3.34 (2 H, m); 6.88 (1 H, dd, J = 3.5 and 1.1 Hz); 6.95 (1 H, dd, J = 5.1 and 3.5 Hz); 7.21 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 4.3; 8.5; 28.7; 32.4; 32.7; 33.7; 35.7; 38.1; 42.6; 44.5; 56.3; 58.1; 123.7; 126.3; 173.4. 317 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.16 (3 H, d, J = 6.1 Hz); 1.42-1.51 (2 H, m); Alkylation/ 365.3, R_(t) = 2.4 1.56-1.81 (4 H, m); 1.95-2.09 (4 H, m); 2.10 (6 H, s); 2.18 (2 H, s); 72% min. 3.21 (2 H, s); 3.30-3.38 (3 H, m); 3.31 (3 H, s); 6.85 (1 H, d, J = 3.5 Hz); 7.04 (1 H, dd, J = 5.0 and 3.6 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 19.0; 32.8; 34.1; 35.6; 38.1; 39.4; 44.3; 56;1; 58.4; 59.3; 74.7; 123.4; 124.8; 126.3; 173.6. 318 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.12 (3 H, d, J = 6.2 Hz); 1.40-1.51 (2 H, m); Alkylation/ 351.3, R_(t) = 2.2 1.72-1.82 (2 H, m); 1.95-2.09 (4 H, m); 2.10 (6 H, s); 2.18 (2 H, s); 54% min. 3.23 (1 H, dd, J = 14.1 and 6.8 Hz); 3.31-3.37 (3 H, m); 3.32 (3 H, s); 3.48-3.55 (1 H, m); 6.85 (1 H, d, J = 3.3 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, br d, J = 5.1 Hz). ¹³C-NMR (CDCl₃): 16.8; 32.6; 32.7; 32.8; 35.8; 39.1; 44.0; 47.4; 56.1; 59.4; 75.9; 123.4; 124.9; 126.3; 174.1. 319 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.35-1.48 (4 H, m); 1.37 (6 H, s); 1.64-1.88 (2 H, Step3/ 354.3, R_(t) = 2.5 m); 2.00-2.16 (2 H, m); 2.02 (6 H, s); 2.17 (2 H, s); 3.39 (2 H, s); Alkylation/ min. 3.55 (2 H, s); 7.23-7.32 (3 H, m); 7.34-7.41 (2 H, m). 12% ¹³C-NMR (CDCl₃): 24.8; 29.9; 32.4; 33.0; 36.3; 37.9; 43.5; 49.0; 50.2; 51.1; 59.5; 59.7; 124.6; 126.7; 127.3; 127.7; 175.3. 320 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.24-1.31 (2 H, m); 1.33 (6 H, s); 1.48-1.70 (4 H, Acylation/ 373.4, R_(t) = 2.9 m); 1.74-2.00 (2 H, m); 2.02 (2.6 H, s); 2.04 (3.4 H, s); 2.13-2.25 40% min. (0.8 H, m); 2.28-2.44 (1.2 H, m); 2.45 (0.8 H, s); 2.47 (1.2 H, s); 3.20 (1.2 H, s); 3.22 (1.8 H, s); 3.38-3.54 (4 H, m); 7.22-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 24.6; 24.8; 29.9; 30.6; 31.0; 31.4; 36.1; 37.6; 38.0; 40.3; 42.3; 43.8; 44.9; 45.5; 45.6; 49.19; 49.23; 55.2; 57.0; 60.6; 60.7; 74.7; 74.8; 126.3; 126.5; 127.57; 127.59; 127.63; 127.70; 137.5; 169.3; 169.4. 321 1 Ex. no. 24a/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.42-1.49 (2 H, m); 1.64-1.78 (4 H, m); 1.82-1.89 Alkylation/ 377.3 (1%) (2 H, m); 1.92-2.01 (2 H, m); 2.02-2.09 (4 H, m); 2.10 (6 H, s); 2.32 64% [MH − NHMe₂]⁺ = (2 H, s); 3.13 (3 H, s); 3.18 (2 H, s); 3.46 (2 H, s); 6.85 (1 H, dd, J = 332.3 (100%), 3.6 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, R_(t) = 2.8 min. J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 12.2; 29.5; 32.7; 35.9; 38.1; 45.0; 49.5; 59.9; 79.7; 123.5; 125.0; 126.3, 174.6. 322 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.31-1.38 (2 H, m); 1.66-1.81 (4 H, m); 1.87-1.93 Step3/ 371.3 (100%) (2 H, m); 1.95-2.03 (2 H, m); 2.06 (6 H, s); 2.09-2.15 (4 H, m); Alkylation/ [MH − NHMe₂]⁺ = 2.35-2.46 (2 H, m); 3.20 (3 H, s); 3.40 (2 H, s); 3.50 (2 H, s); 7.28- 40% 326.3 (73%), 7.32 (3 H, m); 7.38-7.41 (2 H, m). R_(t) = 2.5 min. ¹³C-NMR (CDCl₃): 12.2; 29.6, 30.0; 32.8; 35.9; 37.9; 44.2; 45.0; 49.6; 58.7; 79.8; 126.9; 127.7; 127.9, 174.6. 323 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.13 (3 H, d, J = 6.2 Hz); 1.32-1.42 (2 H, m); Step3/ 345.4, R_(t) = 2.3 1.70-1.79 (2 H, m); 1.86-2.03 (2 H, m); 2.04 (6 H, s); 2.12 (2 H, d, Alkylation/ min. J = 1.3 Hz); 2.15-2.26 (2 H, m); 3.24 (1 H, dd, J = 14.0 and 6.8 Hz); 51% 3.30-3.43 (3 H, m); 3.33 (3 H, s); 3.48-3.56 (1 H, m); 7.26-7.32 (3 H, m); 7.36-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 16.8; 30.1; 32.8; 36.0; 38.0; 44.4; 47.3; 56.1; 59.7; 75.9; 126.8; 127.5; 127.8; 174.1. 324 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.16 (3 H, d, J = 6.1 Hz); 1.32-1 42 (2 H, m); Step3/ 359.4, R_(t) = 2.5 1.55-1.80 (5 H, m); 1.90-2.00 (2 H, m); 2.04 (6 H, s); 2.12 (2 H, s); Alkylation/ min. 2.14-2.28 (1 H, m); 3.26 (2 H, s); 3.30-3.37 (3 H, m); 3.32 (3 H, s); 69% 7.26-7.32 (3 H, m); 7.35-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 19.0; 30.1; 32.9; 34.1, 35.7; 38.0; 39.4; 44.6; 56.1; 58.1; 74.7; 126.6; 127.4; 127.8; 173.6. 325 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.41 (2 H, m); 1.470-1.79 (2 H, m); 1.70- Step3/ 331.3, R_(t) = 2.2 2.02 (2 H, m); 2.04 (6 H, s); 2.12 (2 H, s); 2.13-2.30 (2 H, m); 3.34 Alkylation/ min. (3 H, s); 3.37 (2 H, s); 3.42-3.47 (2 H, m); 3.48-3.53 (2 H, m); 7.27- 53% 7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 30.1; 32.8; 36.0; 38.0; 42.2; 44.4; 58.6; 59.0; 70.7; 126.7; 127.5; 127.8; 173.9. 326 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.20 (3 H, t, J = 7.0 Hz); 1.30-1.41 (2 H, m); 1.54- Step3/ 345.4, R_(t) = 2.3 1.56 (2 H, m); 1.99-2.00 (2 H, m); 2.00 (6 H, s); 2.10 (2 H, s); 2.20 Alkylation/ min. (2 H, br s); 3.38 (2 H, s); 3.44 (2 H, t, J = 5.3 Hz); 3.48 (2 H, q, J = 65% 7.0 Hz); 3.52-3.57 (2 H, m); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 15.2; 30.1; 32.8; 36.0; 38.0; 42.4; 44.5; 59.2; 60.2; 66.2.; 68.6; 126.7; 127.5; 127.8; 173.8. 327 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.20 (3 H, d, J = 6.1 Hz); 1.33-1.46 (2 H, m); Acylation/ 385.3, R_(t) = 2.7 1.57-1.74 (4 H, m); 1.82-2.20 (4 H, m); 2.08 (2.5 H, s); 2.11 (3.5 H, 42% min. s); 2.20-2.27 (1 H, m); 2.58 (1 H, dd, J = 7.2 and 14.8 Hz); 3.24- 3.58 (7 H, m); 3.82-3.94 (1 H, m); 6.83-6.86 (1 H, m); 7.01-7.06 (1 H, m); 7.21-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 19.46; 19.52; 30.9; 31.0; 31.2; 32.7; 33.1; 33.4; 38.1; 40.0; 41.5; 41.9; 42.0; 43.9; 45.3; 56.4; 56.5; 59.7; 74.26; 74.29; 123.3; 123.4; 124.7; 124.9; 126.0; 126.3; 169.9. 328 1 Ex. no. 71/ m/z: [M + H]⁺: = ¹H-NMR (CDCl₃): 1.21 (1.3 H, d, J = 6.1 Hz); 1.22 (1.7 H, J = 6.1 Acylation/ 359.4, R_(t) = 2.8 Hz); 1.24-1.36 (2 H, m); 1.54 (1.2 H, t, J = 7.3 Hz); 1.58-1.70 (2.8 40% min. H, m); 1.72-2.00 (2 H, m); 2.02 (2.6 H, s); 2.03 (3.4 H, s); 2.12-2.40 (3 H, m); 2.52-2.64 (1 H, m); 3.24-3.56 (7 H, m); 3.80-3.94 (1 H, m); 7.20-7.44 (5 H, m). ¹³C-NMR (CDCl₃): 19.46; 19.53; 30.0; 30.1; 30.5; 30.8; 31.0; 31.3; 31.36; 31.40; 35.9; 37.5; 38.0; 38.1; 40.4; 41.5; 42.0; 42.3; 43.8; 45.1; 55.2; 56.3; 56.5; 60.8; 74.3; 77.5; 126.5; 126.7; 127.58; 127.60; 127.67; 127.73; 169.8; 169.9. 329 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.22-1.36 (2 H, m); 1.50-1.70 (4 H, m); 1.78-2.00 Acylation/ 345.3, R_(t) = 2.7 (2 H, m); 2.02 (2.8 H, s); 2.03 (3.2 H, s); 2.14-2.40 (2 H, m); 2.51 (2 50% min. H, dd, J = 12.5 and 6.3 Hz); 3.348 (1.4 H, s); 3.353 (1.6 H, s); 3.37 (1.2 H, s); 3.41 (0.8 H, s); 3.35 (2 H, dd, J = 14.5 and 7.3 Hz); 3.68- 3.73 (2 H, m); 7.22-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 30.1; 30.6; 31.2; 31.4; 34.6; 35.0; 38.0; 38.1; 40.4; 42.3; 43.8; 45.1; 58.7; 58.8; 68.58; 68.60; 126.5; 126.6; 127.55; 127.60; 127.65; 127.71; 169.7. 330 1 Ex. no./168 [M + H]⁺ = 327.3 ¹H-NMR (CDCl₃): 0.04 (2 H, m); 0.39-0.45 (2 H, m); 0.56-0.66 (1 H, N-Demethyl- (22%) m); 1.37 (3 H, dd, J = 14.4 and 7.0 Hz); 1.43-1.53 (2 H, m); 1.73- ation/31% [MH − HNMe]+ = 1.88 (4 H, m); 1.94 (1 H, s); 1.99 (3 H, s); 2.32 (2 H, s); 3.13 (2 H, 296.3 (100%), s); 3.27-3.33 (2 H, m); 7.20-7.26 (1 H, m); 7.31-7.37 (4 H, m). R_(t) = 2.9 min. ¹³C-NMR (CDCl₃): 4.3; 8.5; 28.6; 31.9; 32.4; 32.6; 35.3; 35.7; 42.6; 45.0; 56.7; 57.8; 126.0; 126.5; 128.3; 145.1; 173.5. 331 2 Ex. no. 173/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.40 (1 H , br s); 1.44-1.53 (2 H, m); 1.56-1.69 (4 N-Demethyl- 341.4 (22%) H, m); 1.72-1.98 (8 H, m); 2.00 (3 H, s); 2.02-2.12 (1 H, m); 2.23 (2 ation/60% [MH − HNMe]+ = H, s); 2.24-2.31 (1 H, m); 3.15-3.20 (4 H, m); 7.19-7.27 (2 H, m); 310.3 (100%), 7.34-7.38 (4 H, m). R_(t) = 2.5 min. ¹³C-NMR (CDCl₃): 18.6; 28.2; 28.7; 31.9; 32.5; 33.7; 34.3; 35.8; 40.5; 43.1; 56.8; 59.5; 125.9; 126.5; 128.3; 173.4. 332 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15 (6 H, s); 1.43-1.49 (2 H, m); 1.74-1.80 (2 H, Alkylation/ 365.3 (98%) m); 1.97-2.08 (4 H, m); 2.10 (6 H, s); 2.18 (2 H, s); 3.20 (3 H; s); 36% [MH − NHMe₂]⁺ = 3.26 (2 H; s); 3.41 (2 H, s); 6.85 (1 H, dd, J = 3.6 and 0.9 Hz); 7.04 320.3 (100%), (1 H, dd, J = 5.1 and 3.6 Hz); 7.24 (1 H, dd, J = 5.0 and 0.8 Hz). R_(t) = 2.4 min. ¹³C-NMR (CDCl₃): 22.7; 32.65; 32.74; 35.6; 38.1; 43.9; 49.2; 50.5; 59.4; 76.2; 123.4; 124.9; 126.3; 174.4. 333 1 Ex. no. 50/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.39-1.51 (3 H, m); 1.64-1.93 (10 H, m); 1.94- N-Demethyl- 347.3 (26%) 2.09 (2 H, m); 2.11 (1.4 H, s); 2.13 (1.6 H, s); 2.13-2.20 (2 H, m); ation/ 29% [MH − HNMe]+ = 2.36 (1 H, d, J = 7.4 Hz); 2.37 (1 H, d, J = 7.4 Hz); 2.68-2.80 (1 H, 316.3 (100%), m); 3.28 (1.2 H, s); 3.33 (0.8 H, s); 3.43-3.51 (2 H, m); 6.88-6.91 (1 R_(t) = 2.9 min. H, m); 6.96 (1 H, dt, J = 5.1 and 3.5 Hz); 7.22 (1 H, ddd, J = 5.1, 3.3 and 1.15 Hz). ¹³C-NMR (CDCl₃): 18.74; 18.76; 28.58; 28.62; 28.65; 28.68; 30.79; 30.95; 32.23; 32.37; 34.17; 34.18; 35.82; 38.10; 40.25; 41.24; 41.68; 42.31; 43.90; 45.20; 56.19; 56.76; 56.83; 57.6; 123.70; 123.72; 126.29; 126.44; 171.08. 334 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.12 (3 H, d, J = 6.2 Hz); 1.19 (3 H, t, J = 7.0 Hz); Alkylation/ 365.3, R_(t) = 2.4 1.41-1.51 (2 H, m); 1.73-1.82 (2 H, m); 1.95-2.09 (4 H, m); 2.10 (6 69% min. H, s); 2.18 (2 H, s); 3.17 (1 H, dd, J = 14.0 and 7.2 Hz); 3.31-3.44 (4 H, m); 3.52-3.67 (2 H, m); 6.85 (1 H, br d, J = 3.0 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, br d, J = 5.2 Hz). ¹³C-NMR (CDCl₃): 15.7; 17.6; 32.7; 35.8; 38.1; 44.0; 47.9; 59.3; 60.2; 63.9; 74.1; 123.4; 124.8; 126.3; 174.0. 335 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.13 (3 H, d, J = 6.2 Hz); 1.20 (3 H, t, J = 7.0 Hz); Step3/ 359.4, R_(t) = 2.5 1.30-1.44 (2 H, m); 1.71-1.79 (2 H, m); 1.90-2.02 (2 H, m); 2.03 (6 Alkylation/ min. H, s); 2.12 (2 H, d, J = 1.7 Hz); 2.13-2.25 (2 H, m); 3.18 (1 H, dd, 47% J = 14.0 and 7.2 Hz); 3.33-3.47 (4 H, m); 3.53-3.68 (2 H, m); 7.26- 7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 15.7; 17.6; 30.1, 32.8; 35.9; 38.0; 44.4; 47.9; 60.1; 63.9; 74.1; 126.7; 127.5; 127.7; 174.0. 336 2 Ex. no. 153/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.18 (6 H, s); 1.41-1.50 (2 H, m); 1.63-1.76 (4 H, Alkylation/ 393.4, R_(t) = 2.7 m); 1.85-1.97 (2 H, m); 1.99-2.09 (2 H, m); 2.12 (6 H, s); 2.16 (2 H, 71% min. s); 2.46 (3 H, d, J = 1.0 Hz); 3.19 (3 H, s); 3.21 (2 H, s); 3.28-3.34 (2 H, m); 6.61 (1 H, d, J = 3.5 Hz); 6.66-6.69 (1 H, m). ¹³C-NMR (CDCl₃): 15.2; 24.9; 32.7; 32.8; 35.5; 36.7; 38.1; 38.2; 44.5; 49.1; 49.2; 57.9; 59.4; 73.5; 124.5; 124.9; 137.9; 173.4. 338 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15 (1.4 H, t, J = 7.0 Hz); 1.17 (1.6 H, t, J = 7.0 Acylation/ 373.4, R_(t) = 3.0 Hz); 1.21 (1.4 H, d, J = 6.1 Hz); 1.22 (1.6 H, d, J = 6.1 Hz); 1.24- 30% min. 1.36 (2 H, m); 1.50-1.70 (4 H, m); 1.80--2.0 (2 H, m); 2.02 (3 H, s); 2.03 (3 H, s); 2.14-2.40 (2 H, m); 2.23 (0.5 H, dd, J = 5.7 and 2.2 Hz, overlapped); 2.26 (0.5 H, dd, J = 5.7 and 2.1 Hz, overlapped); 2.58 (0.6 H, dd, J = 13.8 and 6.4 Hz); 2.60 (0.4 H, dd, J = 13.9 and 7.0 Hz); 3.26-3.70 (6 H, m); 3.90-4.01 (1 H, m); 7.20-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 15.61; 15.63; 20.28; 20.32; 29.5; 30.0; 30.7; 30.8; 31.0; 31.4; 36.0; 37.4; 38.0; 38.1; 40.4; 42.0; 42.1; 42.3; 43.8; 45.3; 53.4; 55.1; 56.7; 60.7; 64.09; 64.13; 72.7; 72.8; 126.5; 126.6; 127.58; 127.61; 127.67; 127.72; 137.5; 169.9; 170.1. 339 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.151 (1.4 H, t, J = 7.0 Hz); 1.158 (1.6 H, t, J = 7.0 Acylation/ 379.3, R_(t) = 2.9 Hz); 1.21 (3 H, d, J = 6.1 Hz); 1.33-1.46 (2 H, m); 1.57-1.74 (4 H, 40% min. m); 1.76-2.20 (4 H, m); 2.09 (2.5 H, s); 2.10 (3.5 H, s); 2.22 (0.4 H, dd, J = 5.7 and 2.1 Hz); 2.26 (0.6 H, dd, J = 5.7 and 2.1 Hz); 2.58 (1 H, dd, J = 7.4 and 14.5 Hz); 3.20-3.70 (6 H, m); 3.90-4.00 (1 H, m); 6.83-6.87 (1 H, m); 7.00-7.06 (1 H, m); 7.21-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 15.61; 15.63; 20.27; 20.32; 30.9; 31.1; 31.2; 32.80; 32.83; 33.28; 33.35; 35.6; 36.8; 38.08; 38.09; 40.0; 41.9; 42.0; 42.3; 43.8; 45.2; 53.4; 55.4; 56.7; 59.9; 64.09; 64.13; 72.6; 72.8; 123.3; 123.4; 124.7; 124.9; 126.0, 126.3; 169.9; 170.1. 340 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.15 (6 H, s); 1.34-1.41 (2 H, m); 1.72-1.78 (2 H, Step3/ 359.4 (100%) m); 1.92-2.06 (2 H, m, overlapped); 2.04 (6 H, s); 2.12 (2 H, s); Alkylation/ [MH − NHMe₂]⁺ = 2.15-2.25 (2 H, m); 3.21 (3 H; s); 3.27 (2 H; s); 3.45 (2 H, s); 7.28- 33% 314.3 (99%), 7.30 (3 H, m); 7.37-7.41 (2 H, m). R_(t) = 2.4 min. ¹³C-NMR (CDCl₃): 22.7; 30.2; 32.8; 35.8; 38.0; 44.2; 49.2; 50.4; 60.3; 76.2; 126.7; 127.5; 127.7; 174.5. 341 2 Ex. no. 217/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.43 (1 H, s); 1.49-1.66 (3 H, m); 1.68-2.05 (11 H, N-Demethyl- 377.3 (100%) m); 2.05-2.19 (2 H, m); 2.12 (3 H, s); 2.24 (2 H, s); 3.16 (3 H, s); ation/40% [MH − HNMe]+ = 3.23 (2 H, s); 3.24-3.30 (2 H, m); 6.88 (1 H, dd, J = 3.5 and 1.1 Hz); 346.3 (50%), 6.97 (1 H, dd, J = 5.1 and 3.5 Hz); 7.22 (1 H, dd, J = 5.1 and 1.0 R_(t) = 2.5 min. Hz). ¹³C-NMR (CDCl₃): 12.5; 28.8; 31.3; 32.0; 32.5; 33.7; 35.8; 37.8; 43.5; 49.4; 56.3; 78.3; 123.7; 126.5; 173.4. 342 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.22-1.36 (2 H, m); 1.48-1.68 (4 H, m); 1.72-2.00 Acylation/ 341.3, R_(t) = 2.9 (4 H, m); 2.02 (2.6 H, s); 2.03 (3.4 H, s); 2.06-2.42 (6 H, m); 3.01- 71% min. 3.21 (1 H, m); 3.23 (1.2 H, s); 3.32 (0.8 H, t, J = 7.1 Hz); 3.39 (0.8 H, s); 3.44 (1.2 H, t, J = 7.2 Hz); 7.20-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 18.1; 24.7; 24.65; 24.71; 25.4; 25.4; 30.1; 30.9; 31.0; 31.5; 35.7; 38.0; 38.1; 38.2; 38.3; 39.1; 40.1; 42.2; 43.8; 44.2; 47.8; 55.3; 55.5; 60.7; 126.5; 126.7; 127.59; 127.63, 127.66, 127.73; 137.3; 173.4. 343 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.11 and 1.13 (6 H, 2 d, J = in each case 4.5 Hz); Acylation/ 329.4, R_(t) = 2.8 1.20-1.38 (2 H, m); 1.54 (1.2 H, t, J = 7.3 Hz); 1.58-1.70 (2.8 H, m); 86% min. 1.74-2.00 (2 H, m); 2.02 (2.6 H, s); 2.04 3.4 H, s); 2.14-2.44 (2 H, m); 2.54-2.68 (1 H, m); 3.28 (1.2 H, s); 3.40 (0.8 H, s); 3.42-3.50 (2 H, m); 7.22-7.44 (5 H, m). ¹³C-NMR (CDCl₃): 19.07; 19.08; 30.1; 30.9; 31.0; 31.5; 32.0; 32.2; 35.8; 37.7; 38.0; 38.1; 40.2; 42.1; 44.0; 44.7; 53.4; 55.2; 56.0; 60.8; 126.5; 126.7; 127.58; 127.62; 127.66; 127.75; 137.5; 175.79; 175.83. 344 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.07 (2 H, dd, J = 7.3 and 5.1 Hz); 1.28 (2 H, dd, Alkylation/ 358.3, R_(t) = 2.2 J = 7.3 and 5.1 Hz); 1.46-1.56 (2 H, m); 1.80-1.92 (2 H, m); 2.00- 68% min. 2.15 (4 H, m); 2.10 (6 H, s); 2.23 (2 H, s); 3.35 (2 H, s); 3.47 (2 H, s); 6.85 (1 H, dd, J = 3.5 and 1.0 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 9.3; 13.4; 32.5; 32.6; 36.1; 38.0; 41.0; 43.6; 46.9; 58.6; 59.1; 122.3; 123.3; 124.7; 126.3; 142.8; 174.4. 345 1 Ex. no. 71/ [M + H]⁺ = 357.3, ¹H-NMR (CDCl₃): 0.88-0.98 (2 H, m); 1.08-1.16 (2 H, m); 1.27-1.37 Acylation/ R_(t) = 2.7 min. (2 H, m); 1.50-1.58 (1 H, m); 1.58-1.72 (3 H, m); 1.85-2.01 (2 H, 19% m); 2.05 (6 H, s); 2.16-2.39 (2 H, m); 3.28 (3 H, s); 3.44 (0.8 H, s); 3.49 (1.2 H, t, J = 7.4 Hz); 3.67 (1.2 H, s); 3.74 (0.8 H, t, J = 7.2 Hz); 7.26-7.43 (5 H, m). ¹³C-NMR (CDCl₃): 12.3; 12.5; 29.7; 30.2; 30.6; 31.0; 31.5; 35.3; 38.0; 38.1; 39.7; 42.1; 44.8; 45.2; 56.1; 56.2; 56.5; 64.1; 1266.; 127.6; 127.7; 169.7. 346 1 Ex. no. 333/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.43-1.51 (2 H, m); 1.54-1.71 (8 H, m); 1.77-1.88 Reduction/ 333.3, (4 H, m); 1.90-2.08 (5 H, m); 2.11 (3 H, s); 2.21-2.30 (3 H, m); 2.39 48% [MH − HNMe]+ = (2 H, s); 2.52 (2 H, t, J = 6.9 Hz); 6.88 (1 H, dd, J = 3.5 and 1.1 Hz); 302.3, R_(t) = 1.3 6.94 (1 H, dd, J = 5.1 and 3.5 Hz); 7.20 (1 H, dd, J = 5.1 and 1.1 and 1.7 min. Hz). ¹³C-NMR (CDCl₃): 18.7; 28.4; 28.7; 34.1; 34.5; 36.1; 36.4; 41.0; 54.2; 54.8; 56.5; 66.9; 123.5; 126.2. 347 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.22-1.35 (2 H, m); 1.40-1.50 (5 H, m); 1.60-1.68 Alkylation/ 391.3, R_(t) = 2.4 (2 H, m); 1.70-1.81 (2 H, m); 1.95-2.09 (4 H, m); 2.10 (6 H, s); 2.13 67% min. (2 H, s); 3.19 (2 H, s); 3.30 (2 H, t, J = 7.2 Hz); 3.36 (2 H, dt, J = 11.8 and 2.0 Hz); 3.94 (2 H, br dd, J = 10.5 and 3.2 Hz); 6.85 (1 H, d, J = 3.2 Hz); 7.05 (1 H, dd, J = 5.0 and 3.6 Hz); 7.24 (1 H, d, J = 4.9 Hz). ¹³C-NMR (CDCl₃): 32.7; 32.8; 32.9; 34.1; 35.6; 38.0; 39.6; 44.2; 57.8; 59.2; 67.9; 123.4; 124.9; 126.3; 173.5. 348 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.23-1.52 (7 H, m); 1.60-1.68 (2 H, m); 1.69-1.79 Step3/ 385.4, R_(t) = 2.4 (2 H, m); 1.80-2.03 (2 H, m); 2.05 (6 H, s); 2.13 (2 H, s); 2.14-2.30 Alkylation/ min. (2 H, m); 3.24 (2 H, s); 3.30 (2 H, t, J = 7.2 Hz); 3.36 (2 H, dt, J = 52% 11.8 and 2.2 Hz); 3.95 (2 H, br dd, J = 10.6 and 4.5 Hz); 7.27-7.33 (3 H, m); 7.36-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 30.2; 32.7; 32.8; 32.9; 34.1; 35.7; 38.0; 39.6; 44.5; 57.7; 60.1; 67.9; 126.8; 127.5; 127.8; 173.6. 349 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.07 (2 H, dd, J = 7.5 and 5.1 Hz); 1.29 (2 H, dd, Step3/ 352.3, R_(t) = 2.3 J = 7.4 and 5.1 Hz); 1.37-1.49 (2 H, m); 1.76-1.89 (2 H, m); 1.96- Alkylation/ min. 2.12 (2 H, m); 2.03 (6 H, s); 2.12-2.25 (4 H, m); 3.36 (2 H, s); 3.51 70% (2 H, s); 7.24-7.32 (3 H, m); 7.35-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 9.3; 13.4; 30.2; 32.7; 36.3; 37.9; 43.7; 46.9; 58.5; 60.0; 122.3; 126.6; 127.4; 127.6; 174.3. 350 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.23-1.39 (4 H, m); 1.52-1.73 (6 H, m); 1.80-2.01 Acylation/ 385.4, R_(t) = 2.7 (2 H, m); 2.03 and 2.06 (6 H, 2 s); 2.10-2.26 (4 H, m); 2.32-2.43 (1 62% min. H, m); 3.35 (1 H, s); 3.38-3.49 (5 H, m); 3.90-3.97 (2 H, m); 7.27- 7.42 (5 H, m). ¹³C-NMR (CDCl₃): 30.1; 30.8; 31.2; 31.4; 32.0; 33.10; 33.13; 35.9; 37.5; 38.0; 38.1; 40.3; 41.2; 41.7; 42.3; 43.9; 45.2; 55.2; 56.5; 60.9; 67.9; 126.5; 126.8; 127.6; 127.7; 127.9; 170.4; 170.5. 351 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.20-1.45 (4 H, m); 1.58-1.64 (1 H, m); 1.64-1.74 Acylation/ 391.3, R_(t) = 2.7 (5 H, m); 1.80-2.08 (3 H, m); 2.10 and 2.12 (6 H, 2 s); 2.14-2.28 (4 78% min. H, m); 3.31 (1 H, s); 3.36-3.50 (5 H, m); 3.90-3.97 (2 H, m); 6.83- 6.88 (1 H, m); 7.01-7.08 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 31.1; 31.2; 31.9; 32.0; 32.8; 33.10; 33.14; 33.4; 35.5; 37.0; 38.1; 40.1; 41.3; 41.7; 42.0; 43.9; 45.2; 55.4; 56.6; 59.9; 67.9; 123.3; 123.6; 124.9; 125.1; 126.2; 126.4; 170.40; 170.44. 352 1 Ex. no. 71/ m/z [M + H]⁺ = ¹H-NMR (CDCl₃): 0.84 (2 H, dd, J = 7.1 and 5.1 Hz); 1.24 (2 H, dd, Reductive 338.3, R_(t) = 0.4 J = 7.1 and 5.0 Hz); 1.26-1.35 (2 H, m); 1.47 (2 H, t; J = 6.9 Hz); amination/ min. 1.62-1.76 (2 H, m); 1.77-1.96 (2 H, m); 2.03 (6 H, s); 2.12-2.40 (2 37% H, m); 2.47 (2 H, s); 2.54 (2 H, s); 2.59 (2 H, t, J = 6.9 Hz); 7.23- 7.41 (5 H, m). ¹³C-NMR (CDCl₃): 9.7; 13.1; 28.4; 31.2; 34.3; 38.1; 41.4; 53.4; 60.2; 60.6; 65.4; 123.2; 126.3; 127.6. 353 2 Ex. no. 24b/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.43-1.53 (2 H, m); 1.77-1.87 (2 H, m); 1.90-2.32 Alkylation/ 372.3, R_(t) = 2.4 (8 H, m); 2.10 (6 H, s); 2.22 (2 H, s); 2.43-2.53 (2 H, m); 3.42 (2 H, 73% min. s); 3.62 (2 H, s); 6.84 (1 H, dd, J = 3.5 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, dd, J = 5.1 and 1.0 Hz). ¹³C-NMR (CDCl₃): 16.7; 30.4; 32.4; 32.6; 35.3; 36.0; 38.0; 42.7; 43.3; 48.2; 53.4; 59.3; 123.3; 123.9; 124.8; 126.3; 175.0. 354 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.25-1.35 (2 H, m); 1.53-1.57 (1 H, m); 1.58-1.69 Acylation/ 354.3 (100%) (3 H, m); 1.70-1.80 (2 H, m); 1.83-1.89 (3 H, m); 1.92-2.00 (1 H, 51% [MH − NHMe₂]⁺ = m); 2.01-2.14 (4 H, m, overlapped); 2.03 (4 H, s); 2.04 (2 H, s); 399.4 (87%), 2.20-2.26 (3 H, m); 2.28-2.37 (1 H, m); 3.11 (1 H, s); 3.13 (2 H, s); R_(t) = 4.5 min. 3.35 (1 H, s); 3.41 (1 H, s); 3.46 (2 H, dd, J = 13.4 and 7.0 Hz); 7.27-7.32 (3 H, m); 7;35-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.3; 12.4; 28.1; 28.5; 29.3; 29.4; 30.1; 30.7; 31.2; 31.29; 31.33; 31.5; 36.0; 37.7; 38.0; 38.1; 40.4; 42.3; 44.1; 45.0; 49.2; 49.3, 55.3, 55.4; 78.87; 78.89; 126.5, 126.7; 127.60; 127.65, 127.70; 127.8; 171.9; 172.0. 355 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.35-1.45 (2 H, m); 1.56-1.80 (8 H, m); 1.83-1.89 Acylation/ 405.3 (26%) (2 H, m); 1.92-1.99 (2 H, m); 2.01-2.06 (2 H, m); 2.07-2.13 (2 H, m, 36% [MH − NHMe₂]⁺ = overlapped); 2.10 (3 H, s); 2.11 (3 H, s); 2.20-2.26 (2 H, m); 3.11 360.3 (100%), (1.3 H, s); 3.13 (1.7 H, s); 3.32 (1 H, s); 3.38 (1 H, s); 3.47 (2 H, td, R_(t) = 4.5 min. J = 12.0 and 7.2 Hz); 6.85-6.87 (1 H, m); 7.02-7.06 (1 H, m); 7.22- 7.26 (1 H, m). ¹³C-NMR (CDCl₃): 12.4; 28.1; 28.5; 29.3; 29.4; 31.15; 31.22; 31.3; 32.9; 33.3; 38.1; 40.1; 42.1; 44.1; 45.0; 49.2; 78.9; 123.4; 123.5; 124.9; 126.2; 126.3; 171.9. 356 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.89-0.96 (2 H, m); 1.08-1.15 (2 H, m); 1.35-1.46 Acylation/ 363.3. R_(t) = 2.6 (2 H, m); 1.57-1.64 (1 H, m); 1.64-1.76 (3 H, m); 1.90-2.05 (2 H, 21% min. m); 2.05-2.20 (2 H, m); 2.10 and 2.11 (6 H, 2s); 3.28 (3 H, s); 3.40 (0.8 H, s); 3.51 (1.2 H, t, J = 7.4 Hz); 3.62 (1.2 H, s); 3.76 (0.8 H, t, J = 7.1 Hz); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); 7.02-7.07 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 12.3; 12.5; 30.8; 31.2; 32.9; 33.2; 34.8; 37.2; 38.1; 39.5; 41.9; 44.8; 45.2; 56.1; 56.2; 56.7; 59.9; 64.1; 64.2; 123.3; 123.4; 124.8; 126.1, 126.2; 169.6. 357 2 Ex. no. 162 [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.33-1.45 (2 H, m); 1.72-1.85 (2 H, m); 2.01 (6 H, Step3/ 366.3, R_(t) = 2.4 s); 2.03-2.30 (8 H, m); 2.16 (2 H, s); 2.42-2.53 (2 H, m); 3.44 (2 H, Alkylation/ min. s); 3.62 (2 H, s); 7.24-7.31 (3 H, m); 7.34-7.41 (2 H, m). 67% ¹³C-NMR (CDCl₃): 16.5; 30.0; 30.4; 32.4; 35.3; 36.3; 37.9; 41.0; 43.7; 48.2; 59.0; 59.9; 123.9; 126.7; 127.2; 127.7; 175.1. 358 1 Ex. no. 356/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.44-0.48 (2 H, m); 0.74-0.80 (2 H, m); 1.34-1.44 Reduction/ 349.3, R_(t) = 0.3 (2 H, m); 1.52 (2 H, t, J = 6.8 Hz); 1.66-1.77 (2 H, m); 1.85-2.00 (2 80% min. H, m, 2H); 2.1 (6 H, s); 2.06-2.15 (2 H, m); 2.53 (2 H, s); 2.58 (2 H, s); 2.61 (2 H, t, J = 6.8 Hz); 3.34 (3 H, s); 6.85 (1 H, dd, J = 3.6 and 1.1 Hz); 7.03 (1 H, dd, J = 5.1 and 3.6 Hz); 7.22 (1 H, dd, J = 5.1 and 1.1 Hz,). ¹³C-NMR (CDCl₃): 11.7; 29.7; 33.7; 34.2; 38.1; 41.0; 54.2; 54.6; 59.4; 59.8; 60.3; 66.1; 123.3; 125.0; 126.1. 359 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.23-1.33 (2 H, m); 1.44 (2 H, t, J = 6.9 Hz); 1.65- Reductive 352.4, R_(t) = 0.6 1.75 (2 H, m); 1.80-2.35 (8 H, m); 2.05 (6 H, br s); 2.43-2.52 (2 H, amination/ min. m); 2.57 (2 H, s); 2.62 (2 H, t, J = 6.9 Hz); 2.72 (2 H; s); 7.25-7.42 19% (5 H, m). ¹³C-NMR (CDCl₃): 17.00; 25.9; 30.9; 31.3; 34.1; 36.5; 38.0; 41.6; 54.1; 62.1; 66.1; 124.7; 126.5; 127.5; 127.6. 360 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 6.83 (2 H, dd, J = 7.1 and 5.0 Hz); 1.24 (2 H, dd, Reductive 344.3, R_(t) = 0.5 J = 7.1 and 5.0 Hz); 1.34-1.44 (2 H, m); 153 (2 H, t, J = 8.9 Hz); amination/ min. 1.68-1.80 (2 H, m); 1.84-2.20 (2 H, m); 2.30-2.22 (8 H, m); 2.47 (2 28% H, s); 2.51 (2 H, s); 2.61 (2 H, t, J = 8.9 Hz); 6.86 (1 H, d, J = 3.2 Hz); 7.04 (1 H, d, J = 5.1 and 3.6 Hz); 7.23 (1 H, d, J = 4.9 Hz). ¹³C-NMR (CDCl₃): 9.7; 13.0; 33.7; 34.1; 38.0; 41.1; 53.6; 60.0; 123.2; 124.9; 126.2. 361 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.33-1.43 (2 H, m); 1.56 (2 H, t, J = 6.9 Hz); 1.65- Reductive 358.3, R_(t) = 0.4 1.78 (2 H, m); 1.80-2.26 (8 H, m); 2.10 (6 H, s); 2.42-2.55 (2 H, m); amination/ min. 2.52 (2 H, s); 2.64 (2 H, t, J = 8.9 Hz); 3.80 (2 H, s); 6.85 (1 H, br d, 20% J = 3 Hz); 7.03 (1 H, dd, J = 5.0 and 3.6 Hz); 7.23 (1 H, br d, J = 5 Hz). ¹³C-NMR (CDCl₃): 16.6; 16.9; 28.4; 31.3; 33.4; 33.7; 36.6; 37.4; 38.1; 41.3; 54.0; 62.0; 65.9; 123.3; 124.8; 126.0. 362 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.23-1.37 (2 H, m); 1.56 (1 H, t, J = 7.2 Hz); 1.59- Acylation/ 394.4, R_(t) = 2.9 1.72 (3 H, m); 1.84-1.99 (2 H, m); 2.024 (2.7 H, s); 2.035 (3.3 H, s); 51% min. 2.05-2.40 (10 H, m); 2.44-2.57 (2 H, m); 3.34 (1.1 H, s); 3.40 (0.9 H, s); 3.44 (2 H, m); 7.23-7.32 (3 H, m); 7.33-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 16.7; 30.1; 30.3; 30.7; 31.0; 31.4; 31.8; 32.6; 32.7; 35.3; 35.95; 38.03; 37.5; 37.8; 40.4; 42.2; 44.0; 44.8; 55.2; 56.3; 60.7; 124.23; 124.33; 126.4; 126.7; 127.5; 127.6; 127.67; 127.73; 169.8. 363 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.32-1.46 (2 H, m); 1.58-1.76 (4 H, m); 1.85-2.22 Acylation/ 400.3, R_(t) = 2.9 (16 H, m); 2.30-2.38 (2 H, m); 2.42-2.58 (2 H, m); 3.30 (1.1 H, s); 60% min. 3.36 (0.9 H, s); 3.47 (2 H, m); 6.81-6.87 (1 H, m); 7.00-7.06 (1 H, m), 7.20-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 16.6; 30.1; 30.3; 30.9; 31.2; 31.80; 31.83; 32.71; 32.77; 33.1; 35.3; 35.2; 36.8; 38.0; 38.1; 40.0; 42.1; 44.2; 45.0; 55.4; 56.4; 59.9; 64.1; 123.4; 123.5; 124.28; 124.33; 124.9; 126.0; 126.3; 169.8. 365 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.70-0.78 (2 H, m); 0.95-1.01 (2 H, m); 1.26-1.37 Acylation/ 327.3, R_(t) = 2.7 (2 H, m); 1.52-1.73 (5 H, m); 1.85-2.00 (2 H, m); 2.03 and 2.08 (5 64% min. H, 2 s); 2.15-2.30 (1 H, m); 2.33-2.45 (1 H, m); 3.41 (1 H, s); 3.44- 3.49 (1 H, m); 3.56 (1 H, s); 3.62 (1 H, t, J = 7.2 Hz); 7.24-7.43 (5 H, m). ¹³C-NMR (CDCl₃): 7.3; 7.33; 12.2; 12.5; 30.0; 30.7; 31.3; 31.4; 36.1; 37.6; 38.0; 38.1; 40.3; 42.2; 44.2; 44.9; 54.5; 56.1; 126.5; 127.6; 127.7; 127.9; 172.1; 172.2. 366 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.97 (6 H, t, J = 6.5 Hz); 1.24-1.35 (2 H, m); 1.51- Acylation/ 343.4, R_(t) = 3.0 1.56 (1 H, m); 1.59-1.68 (3 H, m); 1.75-2.03 (2 H, m); 2.04 and 2.07 63% min. (6 H, 2 s); 2.10-2.25 (4 H, m); 2.30-2.45 (1 H, m); 3.36 (1 H, s); 3.40-3.49 (3 H, m); 7.24-7.43 (5 H, m). ¹³C-NMR (CDCl₃): 22.7; 22.73; 25.57; 25.6; 30.0; 30.8; 31.2; 31.4; 36.1; 38.0; 38.1; 40.3; 42.2; 43.3; 43.75; 43.8; 45.2; 55.1; 56.4; 126.5; 127.6; 127.7; 127.8; 171.4; 171.5. 367 1 Ex. no. 364 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.03-0.07 (2 H, m); 0.39-0.43 (2 H, m); 0.67-0.77 Step1/ 335.4 (100%), (1 H, m); 0.91 (3 H, t, J = 7.1 Hz); 1.16-1.68 (16 H, m); 1.71 (1 H, t, Acylation/ R_(t) = 3.0 min. J = 7.2 Hz); 1.78 (1 H, t, J = 7.1 Hz); 2.20 (3 H, s); 2.22 (3 H, s); 45% 2.31-2.36 (2 H, m); 3.23 (1 H, s); 3.28 (1 H, s); 3.49 (2 H, dt, J = 7.2 and 2.7 Hz). ¹³C-NMR (CDCl₃): 4.5; 10.73; 10.74; 14.17; 14.19; 23.7; 23.8; 26.1; 26.6; 28.0; 28.9; 30.17; 30.20; 30.5; 30.6; 30.8; 33.8; 34.4; 34.8; 36.3; 37.3; 37.4; 40.3; 42.2; 44.2; 45.3; 56.5; 58.7, 171.85; 171.89. 368 1 Ex. no. m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.88 (3 H, J = 7.1 Hz); 1.125 (3 H, s); 1.128 (3 H, 364Step1/ 367.4 (100%), s); 1.15-1.42 (10 H, m); 1.49-1.65 (4 H, m); 1.68 (1 H, t, J = 7.3 Acylation/ R_(t) = 2.9 min, Hz); 1.76 (1 H, t, J = 7.1 Hz); 1.79-1.83 (2 H, m); 2.17 (3 H, s); 2.18 17% (3 H, s); 2.21-2.26 (2 H, m); 3.14 (3 H, s); 3.19 (1.2 H, s); 3.25 (0.8 H, s); 3.44-3.48 (2 H, m). ¹³C-NMR (CDCl₃): 14.1; 14.2; 23.7; 23.8; 25.0; 25.1, 26.1; 26.6, 28.0; 28.6, 28.8, 29.1; 30.2; 30.46; 30.52; 30.7; 33.8; 34.0; 34.1; 36.2; 37.29; 37.34; 40.3; 42.2; 44.3; 45.2, 49.15; 49.17; 56.4; 56.5; 56.6; 58.6; 73.90; 73.93; 171.88; 171.91. 389 1 Ex. no. 345/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.44-0.48 (2 H, m); 0.75-0.80 (2 H, m); 1.22-1.34 Reduction/ 343.4, R_(t) = 0.3 (2 H, m); 1.45 (2 H, t, J = 6.8 Hz); 1.64-1.73 (2 H, m); 1.78-1.96 (2 68% min. H, m); 2.03 (6 H, s); 2.20-2.34 (2 H, m); 2.55-2.62 (6 H, m); 3.34 (3 H, s); 7.23-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 11.6 (2 C); 31.13 (2 C); 34.5 (2 C); 38.1 (2 C); 38.3; 41 2; 54.2; 54.7; 59.6; 60.3; 60.6; 66.2; 126.4; 127.6 (2 C); 127.8 (2 C); 136.6. 370 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.92 (6 H, d, J = 6.6 Hz); 1.34-1.60 (5 H, m); Alkylation/ 349.3, R_(t) = 2.6 1.70-1.80 (3 H, m); 1.90-2.09 (3 H, m); 2.11 (6 H, s); 2.17 (2 H, s); 65% min. 3.20 (2 H, s); 3.24-3.30 (2 H, m); 6.85 (1 H, d, J = 3.1 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.24 (1 H, d, J = 5.0 Hz). ¹³C-NMR (CDCl₃): 22.5; 25.9; 32.7; 32.8; 35.5; 36.0; 38.1; 40.7; 44.4; 57.8; 59.3; 123.5; 124.9; 126.3; 173.4. 371 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.84-0.89 (2 H, m); 1.14-1.22 (2 H, m); 1.23-1.36 Acylation/ 380.4, R_(t) = 2.7 (2 H, m); 1.51-1.71 (4 H, m); 1.79-1.85 (2 H, m); 1.86-1.98 (2 H, 62% min m); 2.00 (2.8 H, s); 2.03 (3.2 H, s); 2.12-2.40 (2 H, m); 2.46-2.55 (2 H, m); 3.37 (1.1 H, s); 3.38 (0.9 H, s); 3.40-3.50 (2 H, m); 7.20-7.40 (5 H, m). ¹³C-NMR (CDCl₃): 9.4; 13.97; 13.99; 30.1; 30.2; 30.5; 30.6; 31.0; 31.2; 32.0; 32.5; 35.7; 37.5; 37.9; 38.0; 40.4; 42.2; 44.0; 45.0; 55.2; 56.5; 60.7; 123.16; 123.25; 126.4; 126.6; 127.5; 127.6; 127.69 ; 127.74; 137.0; 169.8; 169.8. 372 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.85-0.90 (2 H, m); 1.17-1.26 (2 H, m); 1.32-1.46 Acylation/ 386.3, R_(t) = 2.7 (2 H, m); 1.56-1.77 (4 H, m); 1.80-1.87 (2 H, m); 1.89-2.05 (4 H, 59% min. m); 2.06-2.25 (6 H, m); 2.49-2.57 (2 H, m); 3.31 (0.4 H, s); 3.36 (1.6 H, s); 3.41-3.55 (2 H, m); 6.83-6.88 (1 H, m); 7.01-7.07 (1 H, m); 7.21-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 9.4; 30.1; 30.2; 31.0; 32.1; 32.5; 32.9; 33.2; 37.1; 38.05; 38.12; 40.0; 40.2; 42.0; 42.1; 43.9; 44.2; 45.1; 45.8; 55.4; 56.8; 59.8; 114.6; 123.2; 123.3; 123.4; 123.5; 124.8; 126.13; 126.18; 126.3; 169.7. 373 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.64-0.68 (2 H, m); 0.83-0.87 (2 H, m); 1.35-1.45 Acylation/ 377.3 (77%) (2 H, m); 1.63 (1.2 H, t, J = 7.2 Hz); 1.66-1.78 (2 H, m, overlapped); 80% [MH − NHMe₂]⁺ = 1.72 (0.8 H, t, J = 7.2 Hz); 1.94-2.21 (4 H, m, overlapped); 2.09 (2.5 332.3 (100%), H, s); 2.11 (3.5 H, s); 2.67 (2 H, d, J = 3.3 Hz); 3.28 (1.2 H, s), 3.30 R_(t) = 2.7 min. (1.8 H, s); 3.37 (0.8 H, s); 3.40 (1.2 H, s); 3.49 (0.8 H, t, J = 7.1 Hz); 3.56 (1.2 H, t, J = 7.1 Hz); 6.84-686 (1 H, m); 7.02-7.06 (1 H, m); 7.22-725 (1 H, m). ¹³C-NMR (CDCl₃): 11.8; 11.87; 11.90; 31.0; 31.2; 32.8; 33.2; 35.4; 37.0; 38.1; 38.4; 38.7, 40.1; 42.1; 44.1; 45.5; 54.42; 54.44; 55.6; 57.2; 59.7; 59.76; 59.81; 123.3; 123.4; 124.8; 125.0; 126.1; 126.3; 169.2; 169.3. 374 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): ): 0.64-0.68 (2 H, m); 0.83-0.88 (2 H, m); 1.32 (2 Acylation/ 371.4 (100%) H, ddd, J = 13.6, 8.0 and 3.0 Hz); 1.56 (1.2 H, t, J = 7.2 Hz); 1.62- 65% [MH − NHMe₂]⁺ = 1.70 (2 H, m, overlapped); 1.65 (0.8 H, t, J = 7.2 Hz); 1.86-1.99 (2 326.3 (87%), H, m); 2.03 (2 H, s); 2.04 (4 H, s); 2.16-2.25 (0.8 H, m); 2.27-2.35 R_(t) = 2.8 min. (1.2 H, m); 2.66 (0.8 H, s), 2.68 (1.2 H, s); 3.28 (1.2 H, s); 3.31 (1.8 H, s); 3.41 (0.8 H, s); 3.44 (1.2 H; s); 3.47 (1.2 H, t, J = 7.2 Hz); 3.54 (0.8 H, t, J = 7.2 Hz); 7.26-7.32 (3 H, m); 7.35-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 11.90; 30.0; 30.7; 31.2; 31.5; 35.8; 37.6; 38.0; 38.1; 38.4; 38.8; 40.3; 42.4; 44.1; 45.5; 54.45; 54.46; 55.4; 57.0; 59.80; 59.83; 60.8; 126.5; 126.7; 127.56; 127.62; 127.68; 127.75; 169.27; 169.31. 375 1 Ex. no. 364 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.2 Hz); 1.16-1.46 (10 H, m); Step1/ 335.4 (100%), 1.51-1.94 (10 H, m); 2.10-2.17 (2 H, m); 2.20 (3 H, s); 2.22 (3 H, s); Acylation/ R_(t) = 3.1 min. 2.35 (2 H, dd; J = 7.4-2.7 Hz); 2.66-2.78 (1 H, m); 3.19 (1.2 H, s); 37% 3.26 (0.8 H, s); 3.43-3.49 (2 H, m). ¹³C-NMR (CDCl₃): 14.16; 14.18; 18.74; 18.75; 23.7; 23.8, 26.1; 26.6; 28.0; 28.57; 28.62; 28.9; 30.2; 30.4; 30.6; 30.8; 32.3; 32.4; 33.8; 36.3; 37.3; 37.4; 40.3; 41.2; 41.6; 42.2; 44.1; 45.3; 56.4; 56.6; 58.7; 171.06; 171.08. 376 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.93 (6 H, d, J = 6.6 Hz); 1.33-1.42 (4 H, m); 1.57 Step3/ 343.4, R_(t) = 2.7 (1 H, td, J = 13.4 and 6.7 Hz); 1.61-1.78 (3 H, m); 1.85-2.03 (1 H, Alkylation/ min. m); 2.05 (6 H, s); 2.12 (2 H, s); 2.14-2.32 (2 H, m); 3.23 (2 H, s); 78% 3.25-3.30 (2 H, m); 7.27-7.32 (3 H, m); 7.36-7.42 (2 H, m). ¹³C-NMR (CDCl₃): 22.5; 25.9; 30.2; 32.9; 35.7; 36.0; 38.0; 40.7; 44.6; 57.7; 126.8; 127.5; 127.8; 173.5. 377 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.90 (6 H, d, J = 6.7 Hz); 1.43-1.52 (2 H, m); Alkylation/ 335.3, R_(t) = 2.4 1.56-1.71 (1 H, m); 1.72-1.82 (2 H, m); 1.84-1.95 (1 H, m); 1.97- 50% min. 2.10 (3 H, m); 2.11 (6 H, s); 2.20 (2 H, s); 3.06 (2 H, d, J = 7.5 Hz); 3.21 (2 H, s); 6.86 (1 H, d, J = 3.0 Hz); 7.05 (1 H, dd, J = 5.1 and 3.5 Hz); 7.25 (1 H, d, J = 4.7 Hz). ¹³C-NMR (CDCl₃): 20.1; 26.7; 32.7; 35.6; 38.0; 40.7; 44.2; 50.0; 59.3; 123.5; 124.9; 126.3; 173.9. 378 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.90 (6 H, d, J = 6.6 Hz); 1.34-1.43 (2 H, m); Step3/ 329.4, R_(t) = 2.4 1.71-1.79 (3 H, m); 1.85-2.02 (3 H, m); 2.04 (6 H, s); 2.15 (2 H, s); Alkylation/ min. 2.16-2.25 (1 H, m); 3.07 (2 H, d, J = 7.5 Hz); 3.24 (2 H, s); 7.26- 63% 7.31 (3 H, m); 7.36-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 20.1; 26.7; 30.2; 32.9; 35.7; 38.0; 44.5; 50.0; 58.6; 126.8; 127.4; 127.8; 174.0. 379 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.75 (2 H, br s); 0.94-1.00 (2 H, m); 1.20-1.35 (2 Acylation/ 371.4, R_(t) = 2.7 H, m); 1.44-1.70 (4 H, m); 1.76-1.98 (2 H, m); 2.04 (6 H, s); 2.21 71% min. (0.6 H, br s); 2.37 (1.4 H, br s); 3.32 (3 H, s); 3.36-3.48 (2 H, m); 3.45 (2 H, s); 3.61 (1.7 H, s); 3.69 (0.3 H, br s); 7.20-7.44 (5 H, m). ¹³C-NMR (CDCl₃): 10.5; 26.5; 29.5, 30.0; 30.6; 30.7; 31.7; 35.9; 38.0; 42.0; 44.3; 44.8; 56.1; 58.7; 77.4; 126.7; 127.7; 170.9. 380 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.20-1.35 (2 H, m); 1.27 (6 H, s); 1.49 (2 H, br s); Acylation/ 373.4, R_(t) = 2.8 1.58-1.68 (2 H, m); 1.91 (2 H, br s); 2.04 (6 H, s); 2.30 (2 H, br s); 76% min. 3.35 (3 H, s); 3.45 (2 H, s); 3.47-3.60 (4 H, m); 7.24-7.44 (5 H, m). ¹³C-NMR (CDCl₃): 22.9; 30.9; 38.0; 43.4; 46.1; 59.3; 80.2; 126.5; 127.7; 127.6; 174.8. 381 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.17-1.33 (2 H, m); 1.42-1.48 (2 H, m); 1.49-2.00 Acylation/ 385.4, R_(t) = 2.9 (8 H, m); 2.03 (6 H, s); 2.14-2.38 (2 H, m); 2.39-2.50; (2 H, m); 65% min. 3.30-3.50 (7 H, m); 3.61 (0.6 H, s); 3.62 (1.4 H, s); 7.22-7.44 (5 H, m). ¹³C-NMR (CDCl₃): 15.3; 28.3; 28.5; 30.1; 30.6; 30.8; 31.6; 35.7; 38.0; 38.1; 38.2; 39.5; 42.4; 44.3; 44.9; 48.7; 48.8; 55.3; 56.3; 59.1; 59.3; 61.1; 77.6; 77.7; 126.5; 127.7; 136.1; 137.3; 174.8; 175.2. 382 1 Ex. no. 18/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.34-1.44 (2 H, m); 1.55-1.76 (6 H, m); 1.77-1.90 Acylation/ 377.3, R_(t) = 2.9 (1 H, m); 1.90-2.10 (3 H, m); 2.11 (6 H, 2 s); 2.14-2.22 (2 H, m); 58% min. 2.50-2.60 (2 H, m); 3.091 and 3.094 (3 H, 2 s); 3.41 and 3.42 (2 H, 2 s); 3.50-3.55 (2 H, m); 6.85-6.89 (1 H, m); 7.02-7.07 (1 H, m); 7.23-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 12.7; 12.8; 29.8; 30.0, 30.1; 30.6; 31.3; 32.9; 33.0; 38.0; 38.1; 39.2; 42.1; 44.6; 44.7; 51.3; 51.4; 55.9; 56.7; 59.9; 81.8; 82.1; 123.3; 123.4; 124.9; 125.0; 126.1; 126.2; 170.5; 170.8. 383 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.74 (2 H, br s); 0.96 (2 H, m); 1.37 (2 H, ddd, J = Acylation/ 377.3, R_(t) = 2.6 13.7, 10.4 and 3.5 Hz); 1.50-1.74 (4 H, m); 1.80-2.02 (2 H, m); 2.11 78% min. (6 H, s); 2.13-2.28 (2 H, m); 3.31 (3 H, s); 3.33-3.39 (2 H, m); 4.49 (2 H, s); 3.57 (1.4 H, br s); 3.71 (0.6 H, br s); 6.84 (1 H, br d, J = 3.2 Hz); 6.99-7.08 (1 H, m); 7.23 (1 H, br d, J = 4.6 Hz). ¹³C-NMR (CDCl₃): 10.5; 26.6; 30.6; 31.4; 32.9; 33.1; 35.5; 37.1; 38.1; 39.6; 41.7; 44.5; 44.9; 56.1; 58.7; 60.2; 77.3; 123.6; 125.2; 126.3; 142.0; 143.7; 170.9. 384 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.25 (6 H, s); 1.32-1.43 (2 H, m); 1.47-1.61 (2 H, Acylation/ 379.3, R_(t) = 2.8 br s); 1.62-1.71 (2 H, m); 1.95 (2 H, br s); 2.02-2.20 (8 H, br s); 76% min. 3.34 (3 H, s); 3.43 (2 H, s); 3.46 (2 H, br s); 3.54 (2 H, very br s); 6.84 (1 H, d, J = 3.0 Hz); 7.03 (1 H, dd, J = 5.1 and 3.5 Hz); 7.23 (1 H, d, J = 4.9 Hz). ¹³C-NMR (CDCl₃): 22.7; 30.7; 33.0; 38.1; 43.4; 46.0; 57.2; 59.1; 59.8; 80.2; 123.4; 124.8; 126.1; 174.6. 385 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.28-1.42 (2 H, m); 1.49-1.55 (2 H, m); 1.56-1.76 Acylation/ 391.3, R_(t) = 2.9 (4 H, m); 1.76-2.24 (12 H, m); 2.35-2.48 (2 H, m); 3.32 (1.4 H, s); 65% min. 3.33 (3 H, s); 3.37 (0.6 H, s); 3.42-3.52 (2 H, m); 3.61 (2 H, s); 8.83 (1 H, dd, J = 3.5 and 0.9 Hz); 7.00-7.05 (1 H, m); 7.20-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 15.24; 15.27; 28.4; 28.5; 30.5; 31.3; 32.9; 33.0; 35.0; 38.1; 39.1; 42.1; 44.3; 44.7; 48.7; 48.8; 55.3; 56.5; 59.0; 59.3; 59.9; 60.1; 77.57; 77.63; 123.1; 123.3; 124.7; 125.1; 126.1; 126.3; 174.8; 175.0. 386 2 Ex. no. 24b/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.40-0.44 (2 H, m); 0.75-0.78 (2 H, m); 1.43-1.49 Alkylation/ 377.3 (100%) (2 H, m); 1.74-1.80 (4 H, m); 1.93-2.13 (4 H, m, overlapped); 2.10 67% [MH − NHMe₂]⁺ = (6 H, s); 2.17 (2 H, s); 3.25 (3 H, s); 3.29 (2 H, s); 3.40-3.43 (2 H, 332.3 (65%), m); 6.85 (1 H, dd, J = 3.8 and 1.1 Hz); 7.04 (1 H, dd, J = 5.1 and 3.6 R_(t) = 2.4 min. Hz); 7.24 (1 H, dd, J = 5.1 and 1.1 Hz). ¹³C-NMR (CDCl₃): 12.0; 30.4; 32.8; 34.5; 38.1; 39.9; 44.4; 53.8; 59.3; 60.0; 123.5; 123.9; 126.3; 173.6. 387 2 Ex. no. 162 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.41-0.44 (2 H, m); 0.76-0.79 (2 H, m); 1.37 (2 H, Step3/ 371.4 (100%) ddd; J = 13.1, 10.4 and 3.0 Hz); 1.71-1.79 (4 H, m); 1.89-2.04 (2 H, Alkylation/ [MH − NHMe₂]⁺ = m, overlapped); 2.03 (6 H, s); 2.12 (2 H, s); 2.15-2.30 (2 H, m); 66% 326.3 (51%), 3.26 (3 H, s); 3.33 (2 H, s); 3.40-3.44 (2 H, m); 7.28-7.30 (3 H, m); R_(t) = 2.5 min. 7.36-7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.1; 30.3; 30.4; 33.0; 35.7; 38.0; 39.9; 44.7; 53.9; 58.8; 60.0; 126.7; 127.5; 127.8; 173.6. 388 1 Ex. no. m/z [M + H]⁺ = ¹H-NMR (CDCl₃): 0.92 (3 H, dt, J = 7.2 and 2.0 Hz); 1.22-1.33 (8 H, 364Step1/ 365.4 (100%), m);); 1.37-1.44 (2 H, m); 1.55-1.74 (8 H, m, overlapped); 1.70 (1 H, Acylation/ R_(t) = 3.0 min. t, J = 7.3 Hz, overlapped); 1.77 (1 H, t, J = 7.1 Hz); 2.12-2.19 (2 H, 29% m); 2.22-2.30 (6 H, m); 2.58 (0.8 H, s); 2.60 (1.2 H, br. s); 3.23 (3 H, s); 3.30 (1 H, s); 3.35 (1 H, br s); 3.49-3.57 (2 H, m). ¹³C-NMR (CDCl₃): 12.57; 12.59; 14.1; 14.2; 23.71; 23.74; 26.0; 26.6; 27.9; 28.7; 30.1; 30.5; 30.6; 30.8; 34.2; 36.5; 37.4; 40.2; 40.4; 40.6; 42.1; 44.2, 45.8; 50.20; 50.23; 79.47; 79.52; 169.5; 169.6. 389 1 Ex. no. m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.91 (3 H, J = 7.3 = Hz); 1.18-1.69 (14 H, m); 1.71 364Step1/ 351.4 (100%), (1 H, t, J = 7.2 Hz); 1.79 (1 H, t, J = 7.1 Hz); 2.10-2.19 (2 H, m); Acylation/ R_(t) = 2.7 min. 2.21 (3 H, s), 2.25 (3 H, br s); 2.28-2.39 (2 H, m); 2.64-2.76 (1 H, 41% m); 3.21 (1 H, br s); 3.28 (1 H, s); 3.40-3.36 (2 H, m); 3.50 (1 H, t, J = 7.3 Hz); 3.71-3.77 (1 H, m); 3.82-3.88 (1 H, m); 3.94-3.98 (1 H, m). ¹³C-NMR (CDCl₃): 14.1; 14.2, 23.7; 23.8; 26.1; 26.7; 28.0; 28.91; 28.93; 30.1; 30.2; 30.4; 30.5, 30.7; 32.3; 33.9; 35.36; 35.41; 36.1; 37.4; 38.1; 38.4, 40.3; 42.2; 44.2; 45.3, 56.5; 58.5; 67.6; 73.32; 73.35; 170.4; 170.5. 390 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.22-1.35 (2 H, m); 1.47-1.53 (1 H, m); 1.55-1.75 Acylation/ 371.4, R_(t) = 3.0 (4 H, m); 1.80-2.00 (4 H, m); 2.03 and 2.04 (6 H, 2 s); 2.06-2.20 (2 62% min. H, m); 2.23-2.34 (1 H, m); 2.51-2.60 (2 H, m); 3.09 (3 H, s); 3.43 and 3.45 (2 H, 2 s); 3.47-3.53 (2 H, m); 7.27-7.33 (3 H, m); 7.34- 7.40 (2 H, m). ¹³C-NMR (CDCl₃): 12.7; 12.8; 30.0; 30.1; 30.2; 30.5; 30.8; 31.6; 35.1; 38.0; 38.1; 39.5; 42.4; 44.6; 44.7; 51.3; 51.4; 55.8; 56.5; 60.9; 81.8; 82.1; 126.5; 126.7; 127.6; 127.7; 127.74; 170.5; 170.8. 391 1 Ex. no. 31/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.70-0.78 (2 H, m); 0.94-0.99 (2 H, m); 1.35-1.44 Acylation/ 391.3, R_(t) = 2.9 (2 H, m); 1.53-1.70 (4 H, m); 1.73-1.97 (3 H, m); 2.00-2.10 (1 H, 65% min. m); 2.13 (6 H, br s); 2.46 (3 H, s); 3.32 (3 H, s); 3.42-3.50 (2 H, m); 3.44 (2 H, s); 3.57 (2 H, br s); 6.59-6.64 (1 H, m); 6.65-6.70 (1 H, m). ¹³C-NMR (CDCl₃): 10.5; 15.2; 26.6; 30.8; 31.5; 32.7; 33.1; 35.7; 38.1; 41.8; 44.5; 45.0; 50.8; 56.1; 58.7; 60.3; 77.4; 124.5; 125.2; 137.9; 171.0. 392 1 Ex. no. 31/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.32-1.42 (2 H, m); 1.49-1.62 (3 H, m); 1.63-1.96 Acylation/ 405.3, R_(t) = 3.0 (6 H, m); 1.97-2.08 (3 H, m); 2.10 and 2.13 (6 H, 2 s); 2.37-2.45 (2 62% min. H, m); 2.46 (3 H, s); 3.33 (3 H, s); 3.32 and 3.37 (2 H, 2 s); 3.42- 3.52 (2 H, m); 3.62 (2 H, s); 6.57-6.63 (1 H, m); 6.64-6.69 (1 H, m). ¹³C-NMR (CDCl₃): 15.2; 28.4; 28.5; 30.7; 31.6; 32.7; 33.0; 35.4; 38.1; 39.2; 42.3; 44.3; 44.9; 48.7; 48.8; 55.3; 58.5; 59.1; 59.3; 60.0; 77.6; 124.3; 124.5; 124.8; 125.1; 137.7; 175.0; 175.2. 393 1 Ex. no. 31/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.26 (6 H, s); 1.39 (2 H, ddd, J = 13.6 and 10.3 Acylation/ 393.3, R_(t) = 3.0 and 3.5 Hz); 1.50-1.72 (5 H, m); 1.81-1.97 (2 H, m); 1.81-1.97 (2 60% min. H, m); 2.00-2.10 (1 H, m); 2.12 (6 H, s); 2.47 (3 H, s); 3.35 (3 H, s); 3.44 (2 H, br s); 3.54 (2 H, br s); 6.60-6.64 (1 H, m); 6.66-6.70 (1 H, m). ¹³C-NMR (CDCl₃): 15.2; 22.9; 30.9; 33.0; 38.1; 43.5; 46.2; 56.8; 59.2; 60.1; 80.2; 124.4; 125.0; 137.8; 174.8. 394 1 Ex. no. 71/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.24-1.34 (2 H, m); 1.36 (2.7 H, s); 1.38 (3.3 H, s); Acylation/ 382.4, R_(t) = 2.8 1.53-1.59 (1.1 H, m); 1.60-1.72 (2.9 H, m); 1.84-1.98 (4 H, m); 2.03 51% min. (2.7 H, s); 2.05 (3.3 H, s); 2.14-2.37 (2 H, m); 2.38-2.48 (2 H, m); 3.36 (1.1 H, s); 3.40 (0.9 H s); 3.46 (2 H, t, J = 7.0 Hz); 7.22-7.42 (5 H, m). ¹³C-NMR (CDCl₃): 26.5; 30.1; 30.2; 30.6; 30.7; 31.2; 31.4; 31.8; 31.9; 32.00; 32.02; 35.5; 35.7; 37.5; 37.9; 38.0; 40.37; 40.41; 42.2; 44.2; 44.9; 55.2; 58.4; 60.9; 124.5; 124.7; 126.4; 126.8; 127.4; 127.6; 127.7; 127.8; 137.0; 169.8. 395 1 Ex. no. 18/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 1.34-1.46 (2 H, m); 1.36 (2.7 H, s); 1.37 (3.3 H, s); Acylation/ 388.3, R_(t) = 2.8 1.58-1.76 (4 H, m); 1.85-2.04 (4 H, m); 2.05-2.21 (2 H, m); 2.09 64% min. (2.7 H, s); 2.12 (3.3 H, s); 2.38-2.47 (2 H, m); 3.32 (1.2 H, s); 3.36 (0.8 H, s); 3.48 (2 H, t, J = 7.2 Hz); 6.82-6.88 (1 H, m); 7.01-7.07 (1 H, m); 7.21-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 26.4; 26.5; 30.0; 30.2; 30.6; 31.0; 31.2; 31.8; 31.9; 32.0; 32.9; 33.1; 35.1; 35.6; 35.7; 36.8; 37.9; 38.1; 40.0; 42.1; 44.2; 44.9; 55.4; 56.4; 59.9; 123.4; 123.6; 124.60; 124.64; 124.9; 126.2; 126.2; 169.8. 396 1 Ex. no. 425/ m/z: [MH − ¹H-NMR (CDCl₃): 0.70-0.78 (2 H, m); 0.93-1.00 (2 H, m); 1.32-1.42 Acylation/ HNMe₂]⁺ = 366.2 (2 H, m); 1.54-1.70 (4 H, m); 1.80-2.00 (4 H, m); 2.04-2.10 (1 H, 24% (100%), R_(t) = 3.0 m); 2.13 (6 H, br s); 3.32 (3 H, s); 3.42 (2 H, s); 3.44-3.50 (1 H, m); min. 3.54-3.76 (2 H, m); 6.61 (1 H, br d, J = 3.6 Hz); 8.84 (1 H, br d, J = 2.7 Hz). ¹³C-NMR (CDCl₃): 10.5; 28.6; 30.6; 31.3; 32.4; 32.8; 35.4; 38.0; 41.8; 44.4; 44.9; 56.1; 58.7; 60.4; 77.5; 124.6; 125.5; 171.0. 397 1 Ex. no. 425/ m/z: [MH − ¹H-NMR (CDCl₃): 1.30-1.41 (2 H, m); 1.52-1.77 (6 H, m); 1.78-2.08 Acylation/ HNMe₂]⁺ = 380.2 (6 H, m); 2.10 and 2.11 (6 H, 2 s); 2.37-2.48 (2 H, m); 3.33 and 24% (100%), R_(t) = 3.2 3.37 (5 H, 2 s); 3.44-3.57 (2 H, m); 3.62 (2 H, s); 6.60 (1 H, d, J = min. 3.8 Hz); 6.82-6.86 (1 H, m). ¹³C-NMR (CDCl₃): 15.3; 28.4; 28.5; 30.5; 31.4; 32.5; 32.7; 35.2; 38.1; 39.2; 42.2; 44.3; 44.9; 48.7; 48.8; 55.4; 56.5; 59.1; 59.3; 60.5; 77.6; 77.7; 124.5; 125.4; 125.5; 127.8; 175.0; 175.2. 398 1 Ex. no. 425/ m/z: [MH − ¹H-NMR (CDCl₃): 1.26 (6 H, s); 1-34-1.42 (2 m); 1.50-1.70 (5 H, m); Acylation/ HNMe₂]⁺ = 368.2 1.80-1.95 (2 H, m); 1.95-2.10 (2 H, m); 2.11 (6 H, s); 3.35 (3 H, s); 28% (100%), R_(t) = 3.1 3.44 (2 H, s); 3.44-3.60 (3 H, m); 6.60 (1 H, br d, J = 3.5 Hz); 6.84 min. (1 H, br d, J = 3.6 Hz). ¹³C-NMR (CDCl₃): 22.9; 30.7; 31.5; 32.7; 37.9; 38.0; 43.6; 46.2; 57.5; 59.2; 60.4; 80.2; 124.4; 125.2; 125.5; 174.8. 399 1 Ex. no. 432/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.2 Hz); 1.10-1.45 (10 H, m); Alkylation/ 351.4, R_(t) = 2.6 1.46-1.80 (7 H, m); 2.20-2.18 (2 H, m); 2.19 (6 H, s); 2.23 (2 H, m); 76% min. 3.13 (2 H, s); 3.26-3.30 (2 H, m); 3.35 (1 H, dd; J = 8.3 and 6.9 Hz); 3.72 (1 H, dd, J = 15.4 and 7.7 Hz); 3.80-3.92 (2 H, m). ¹³C-NMR (CDCl₃): 14.2; 23.6; 26.5; 28.2; 30.7; 30.6; 32.1; 32.4; 35.5; 36.8; 37.3; 41.5; 45.3; 55.8; 57.6; 67.7; 73.0; 76.7; 77.0; 77.2; 173.9. 400 2 Ex. no. 433/ [M + H]⁺ m/z = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.1 Hz); 1.10-1.42 (10 H, m); Alkylation/ 351.4, R_(t) = 2.4 1.46-1.80 (7 H, m); 2.02-2.19 (2 H, m); 2.20 (6 H, s); 2.26 (2 H, s); 59% min. 3.10 (2 H, s); 3.26 (2 H, t, J = 7.4 Hz); 3.35 (1 H, dd, J = 8.3 and 6.9 Hz); 3.70-3.77 (1 H, m); 3.80-3.93 (2 H, m). ¹³C-NMR (CDCl₃): 14.0; 23.8; 26.5; 28.5; 30.4; 30.6; 31.8; 32.3; 35.9; 36.8; 37.3; 41.2; 43.2; 56.0; 59.8; 67.9; 73.2; 173.7. 401 1 Ex. no. 432/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.87 (2 H, m); 0.91 (3 H, t, J = 7.2 Hz); 1.10-1.44 Alkylation/ 346.4, R_(t) = 2.6 (12 H, m); 1.52-1.64 (2 H, m); 1.66-1.80 (4 H, m); 2.20 (6 H, s); 67% min. 2.25 (2 H, s); 3.26 (2 H, s); 3.46 (2 H, m). ¹³C-NMR (CDCl₃): 7.8; 13.9; 14.2; 23.8; 26.4; 28.4; 30.7; 30.8; 31.8; 32.1; 32.6; 35.7; 37.2; 41.1; 45.2; 55.8; 58.7; 123.0; 174.4. 402 2 Ex. no. 433/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.83-0.88 (2 H, m); 0.90 (3 H, t, J = 7.1 Hz); 1.12- Alkylation/ 346.4, R_(t) = 2.3 1.45 (12 H, m); 1.50-1.84 (6 H, m); 2.20 (6 H, s); 2.27 (2 H, s); 3.22 37% min. (2 H, s); 3.47 (2 H, t, J = 7.2 Hz). ¹³C-NMR (CDCl₃): 7.5; 14.1; 14.0; 23.8; 26.5; 28.6; 30.6; 31.8; 32.5; 36.0; 37.3; 41.1; 43.0; 56.0; 60.7; 122.8; 174.2. 403 1 Ex. no. 432/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.2 Hz); 1.12-1.44 (8 H, m); 1.52- Alkylation/ 360.4, R_(t) = 2.8 1.64 (2 H, m); 1.67-1.77 (2 H, m); 1.92-1.98 (2 H, m); 1.92-1.98 (2 57% min. H, m); 1.99-2.18 (4 H, m); 2.19 (6 H, s); 2.24 (2 H, s); 2.43-2.58 (2 H, m); 3.19 (2 H, s); 3.34-3.40 (2 H, m). ¹³C-NMR (CDCl₃): 14.2; 16.9; 23.8; 26.4; 28.4; 30.5; 32.0; 33.7; 34.7; 35.6; 37.3; 39.1; 45.2; 53.4; 55.9; 58.0; 124.2; 174.1. 404 2 Ex. no. 433/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.1 Hz); 1.10-1.45 (10 H, m); Alkylation/ 360.4, R_(t) = 2.6 1.46-1.82 (4 H, m); 1.88-2.24 (6 H, m); 2.21 (6 H, s); 2.27 (2 H, s); 57% min. 2.48-2.58 (2 H, m); 3.16 (2 H, s); 3.33-3.41 (2 H, m). ¹³C-NMR (CDCl₃): 14.5; 17.2; 24.1; 26.8; 28.9; 30.9; 32.1; 32.3; 34.0; 35.2; 36.2; 37.6; 39.3; 43.4; 56.2; 60.5; 124.5; 174.4. 405 1 Ex. no. 71/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.40-0.46 (2 H, m); 0.70-0.77 (2 H, m); 1.20-1.36 Acylation/ 385.4, R_(t) = 2.9 (2 H, m); 1.52-1.57 (2 H, m); 1.60-1.70 (2 H, m); 1.85-2.00 (4 H, 60% min. m); 2.03 and 2.05 (6 H, 2 s); 2.17-2.36 (2 H, m); 2.41-2.48 (2 H, m); 3.23 and 3.25 (3 H, 2 s); 3.39 and 3.40 (2 H, 2 s); 3.43-3.50 (2 H, m); 7.26-7.33 (3 H, m); 7.34-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 12.27; 12.3; 28.0; 28.1; 30.1; 30.6; 30.64; 31.0; 31.3; 31.4; 36.0; 37.6; 38.0; 38.1; 40.4; 42.3; 44.0; 45.0; 53.75; 55.2; 56.4; 60.9; 61.56; 61.59; 126.5; 126.7; 127.6; 127.63; 127.7; 127.74; 171.7. 406 1 Ex. no. 432/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.1 Hz); 1.10-1.40 (10 H, m); Alkylation/ 365.4, R_(t) = 2.9 1.52-1.80 (6 H, m); 1.82-1.94 (4 H, m); 2.06-2.18 (2 H, m); 2.21 (6 66% min. H, s); 2.24 (2 H, s); 3.16 (3 H, s); 3.18 (2 H, s); 3.23-3.29 (2 H, m). ¹³C-NMR (CDCl₃): 12.5; 14.2; 23.8; 26.5; 28.4; 30.8; 31.2; 32.0; 32.2; 35.5; 37.4; 37.9; 45.4; 49.3; 56.8; 58.4; 78.3; 173.8. 407 1 Ex. no. 426/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.31-1.42 (2 H, m); 1.54-2.04 (14 H, m); 2.11 (2 Acylation/ 409.3 (58%) H, s); 2.12 (4 H, s); 2.39-2.46 (2 H, m); 3.33 (3 H, s); 3.44-3.53 (2 91% [MH − NHMe₂]⁺ = H, m); 3.62 (2 H, s); 6.36-6.39 (1 H, m); 6.41-6.43 (1 H, m). 364.3 (100%), ¹³C-NMR (CDCl₃): 15.3; 28.45; 28.52; 30.6; 31.4; 32.2; 32.5; 35.2, R_(t) = 3.0 min, 38.1; 39.3; 42.3; 44.3; 44.9, 45.3, 47.3, 48.7, 48.8, 55.4; 56.5, 59.1; 59.3; 77.6; 77.7; 106.0; 106.2; 106.3; 121.4; 162.5, 165.4, 175.2. 409 2 Ex. no. 433/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.89 (3 H, t, J = 7.2 Hz); 1.10-1.42 (10 H, m); Alkylation/ 337.3, R_(t) = 2.1 1.52-1.62 (2 H, m); 1.66-1-78 (2 H, m); 1.87 (2 H, dd, J = 14.5 and 43% min. 7.4 Hz); 2.19 (6 H, s); 2.24 (2 H, s); 2.90-3.02 (1 H, m); 3.09 (2 H, s); 3.18 (2 H, t, J = 7.1 Hz); 4.37 (2 H, t, J = 6.1 Hz); 4.77 (2 H, dd, J = 7.7 and 5.9 Hz). ¹³C-NMR (CDCl₃): 14.0; 23.6; 26.6; 28.6; 30.5; 31.2; 31.8; 32.9; 35.7; 37.1; 40.0; 43.1; 55.9; 59.9; 77.5; 173.9. 410 1 Ex. no. 432/ [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.91 (3 H, t, J = 7.2 Hz); 1.10-1.40 (10 H, m); Alkylation/ 337.4, R_(t) = 2.5 1.52-1.64 (2 H, m); 1.66-1.78 (2 H, m); 1.89 (2 H, dd, J = 14.5 and 35% min. 7.5 Hz); 2.20 (6 H, s); 2.23 (2 H, s); 2.90-3.02 (1 H, m); 3.14 (2 H, s); 3.19 (2 H, t, J = 7.1 Hz); 4.38 (2 H, t, J = 6.1 Hz); 4.78 (2 H, dd, J = 7.7 and 6.0 Hz). ¹³C-NMR (CDCl₃): 14.2; 23.8; 26.4; 28.4; 30.7; 31.1; 32.0; 33.0; 35.5; 37.2; 40.2; 45.1; 55.8; 57.7; 77.6; 173.9. 411 1 Ex. no. 426/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.72-0.76 (2 H, m); 0.94-0.98 (2 H, m); 1.35-1.42 Acylation/ 395.3 (55%) (2 H, m); 1.58-1.68 (4 H, m); 1.82-1.95 (2 H, m); 1.95-2.15 (2 H, m, 45% [MH − NHMe₂]⁺ = overlapped); 2.12 (6 H, s); 3.32 (3 H, s); 3.33-3.40 (0.7 H, m); 3.43- 350.2 (100%), 3.50 (1.1 H, m, overlapped); 3.44 (2 H, s); 3.56 (1.3 H, br. s); 3.72 R_(t) = 2.7 min. (0.7 H, br. s); 6.36-6.40 (1 H, m); 6.41-6.43 (1 H, m). ¹³C-NMR (CDCl₃): 10.5; 26.6; 30.6; 31.4; 32.1; 32.6; 35.5; 38.1; 41.9; 44.5; 56.2, 58.7; 60.2; 77.5; 106.3; 121.3; 126.5; 165.4; 171.0. 412 1 Ex. no. 18/ m/z [M + H]⁺ = ¹H-NMR (CDCl₃): 0.41-0.46 (2 H, m); 0.71-0.77 (2 H, m); 1.23-1.45 Acylation/ 391.3, R_(t) = 2.8 (2 H, m); 1.58-1.74 (5 H, m); 1.87-2.08 (4 H, m); 2.09 and 2.11 (6 29% min. H, 2 s); 2.13-2.22 (1 H, m); 2.41-2.48 (2 H, m); 3.23 and 3.25 (3 H, 2 s); 3.36 and 3.37 (2 H, 2 s); 3.49 (2 H, q, J = 7.2 Hz); 6.84-6.87 (1 H, m); 7.02-7.06 (1 H, m); 7.22-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 12.28; 12.3; 28.0; 28.1; 30.6; 31.0; 31.1; 31.2; 32.9; 33.2; 35.6; 37.1; 38.1; 38.11; 40.2; 42.0; 44.0; 45.1; 53.75; 53.77; 55.4; 56.5; 59.9; 61.57; 61.6; 123.4; 124.9; 126.2; 126.3; 171.7. 413 2 Ex. no. 433; [M + H]⁺: m/z = ¹H-NMR (CDCl₃): 0.90 (3 H, t, J = 7.1 Hz); 1.10-1.46 (10 H, m); Alkylation/ 365.4, R_(t) = 2.7 1.50-1.92 (12 H, m); 2.05-2.16 (2 H, m); 2.20 (6 H, s); 2.26 (2 H, s); 36% min. 3.15 (3 H, s); 3.22-3.28 (2 H, m). ¹³C-NMR (CDCl₃): 12.5; 14.0; 23.8; 26.5; 28.7; 29.7; 30.4; 31.3; 31.8; 35.7; 37.2; 37.6; 41.0; 43.4; 49.4; 56.1; 60.1; 78.3; 173.7. 414 2 Ex. no. 408 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.27-1.37 (2 H, m); 1.57-1.75 (4 H, m); 1.75-1.92 Step1/ 355.4, R_(t) = 3.0 (4 H, m); 1.93-2.03 (1 H, m); 2.04 (6 H, s); 2.06-2.22 (5 H, m); 2.26 Acylation/ min. (1 H, d, J = 7.4 Hz); 2.34 (1 H, d, J = 7.4 Hz); 2.62-2.76 (1 H, m); 44% 3.07 and 3.14 (2 H, 2 s); 3.48 (2 H, t, J = 7.2 Hz); 3.50 (2 H, t, J = 7.2 Hz); 7.28-7.32 (3 H, m); 7.33-7.41 (2 H, m). ¹³C-NMR (CDCl₃): 18.69; 18.74; 28.5; 28.6; 30.4; 30.5; 31.1; 31.11; 32.27; 32.34; 34.3; 36.0; 38.0; 40.2; 41.2; 41.6; 42.3; 44.0; 45.3, 56.2; 58.1; 60.7; 128.6; 127.4; 127.5; 127.86; 127.72; 171.0. 415 2 Ex. no. 25/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.36-1.46 (2 H, m); 1.63-1.74 (2 H, m); 1.77 (1 H, Acylation/ 351.3, R_(t) = 2.4 t, J = 7.2 Hz); 1.85 (1 H, t, J = 7.2 Hz); 196-2.09 (4 H, m); 2.10 (6 46% min. H, s); 2.45 (1 H, t, J = 6.4 Hz); 2.51 (1 H, t, J = 6.6 Hz); 3.18 and 3.24 (2 H, 2 s); 3.31 and 3.34 (3 H, 2 s); 3.48-3.55 (2 H, m); 3.66 (1 H, t, J = 6.4 Hz); 3.69 (1 H, t, J = 6.6 Hz); 6.80-6.86 (1 H, m); 7.00- 7.06 (1 H, m); 7.20-7.25 (1 H, m). ¹³C-NMR (CDCl₃): 30.9; 33.1; 34.7; 35.1; 36.3; 38.1; 40.1; 42.1; 44.1; 45.2; 55.9; 57.5; 58.8; 58.9; 59.7; 68.6; 123.4; 124.8; 126.17; 126.24; 143.0; 169.58; 169.61. 416 2 Ex. no. 25/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.92 (3 H, d, J = 6.3 Hz); 0.95 (3 H, d, J = 6.3 Hz); Acylation/ 349.3, R_(t) = 2.9 1.37-1.45 (2 H, m); 1.62-1.74 (2 H, m); 1.77 (1 H, t, J = 7.2 Hz); 65% min. 1.85 (1 H, t, J = 7.1 Hz); 2.00-2.10 (5 H, m); 2.109 and 2.11 (6 H, 2 s); 2.12-2.20 (2 H, m); 3.15 and 3.24 (2 H, 2 s); 3.46-3.55 (2 H, m); 6.82-6.87 (1 H, m); 7.00-7.06 (1 H, m); 7.21-7.26 (1 H, m). ¹³C-NMR (CDCl₃): 22.6; 22.7; 25.5; 25.6; 30.9; 33.1; 34.4; 36.3; 38.1; 40.0; 42.1; 43.3; 43.7; 44.1; 45.4; 56.0; 57.7; 59.8; 123.4; 124.9; 126.2; 126;3; 143.0; 171.38; 17144. 418 1 Ex. no. 426/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.26 (6 H, s); 1.34-1.42 (2 H, m); 1.55-1.68 (4 H, Acylation/ 397.3 (41%) m); 1.84-1.91 (2 H, m); 1.96-2.05 (2 H, m); 2.12 (6 H, s); 3.35 (3 H, 73% [MH − NHMe₂]⁺ = s); 3.43 (2 H, s); 3.45 (2 H, s); 3.56 (2 H, br. s); 6.37-6.39 (1 H, m); 352.3 (100%), 6.41-6.43 (1 H, m). R_(t) = 2.9 min. ¹³C-NMR (CDCl₃): 22.9; 30.7; 32.5; 38.1; 43.6; 46.2; 53.4; 57.2; 59.3; 60.1; 80.2; 106.2; 106.3; 110.0; 121.1; 162.5; 165.4; 174.8. 552 2 Ex. no. 86/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 1.34-1.46 (2 H, m); 1.45-1.64 (1 H, m); 1.64-1.98 N-Demethyl- 341.3 (88%) (11 H, m); 2.00 (1.3 H, s); 2.01 (1.7 H, s); 2.02-2.10 (1 H, m); 2.20- ation/ [MH − H2NMe]+ = 2.10 (2 H, m); 2.36 (1 H, d, J = 7.3 Hz); 2.38 (1 H, d, J = 7.3 Hz); 34% 310.3 (100%), 2.70-2.80 (1 H, m); 3.30 (1.2 H, s); 3.34 (0.8 H, s); 3.43-3.51 (2 H, R_(t) = 3.0 min. m); 7.20-7.28 (1 H, m); 7.32-7.44 (4 H, m). ¹³C-NMR (CDCl₃): 4.4; 6.88; 6.99; 28.6; 30.7; 31.0; 32.2; 32.3; 34.0; 35.6; 39.5; 39.9; 40.3; 42.4; 44.1; 45.2; 56.8; 57.3; 58.1; 126.1; 126.3; 126.5; 128.3; 128.4; 128.5; 171.41; 171.45. 521 2 Ex. no. 417 m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.40-0.43 (2 H, m); 0.75-0.78 (2 H, m); 1.43-1.49 Step6/ 395.3 (100%) (2 H, m); 1.72-178 (4 H, m); 191-197 (4 H, m); 2.11 (6 H, s); 2.19 Alkylation/ [MH − NHMe₂]⁺ = (2 H, s); 3.25 (3 H, s); 3.28 (2 H, s); 3.39-3.43 (2 H, m); 6.39 (1 H, 85% 350.3 (37%), dd, J = 4.0 and 1.7 Hz); 6.42 (1 H, m). R_(t) = 2.6 min. ¹³C-NMR (CDCl₃): 12.1; 30.4; 32.2; 32.7; 35.5; 38.0; 39.9; 44.4; 53.9; 58.9; 59.5; 60.0; 106.3; 106.4; 121.1; 162.5; 165.4; 173.5. 422 1 Ex. no. 85/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.12-0.21 (2 H, m); 0.53-0.59 (2 H, m); 1.05-1.15 N-Demethyl- 327.3 (76%) (1 H, m); 1.34-1.46 (2 H, m); 1.64-1.79 (4 H, m); 1.79-1.87 (2 H, ation/ [MH − H2NMe]+ = m); 1.96-2.10 2 H, m); 2.01 (3 H, s); 2.20 (2 H, t, J = 6.5 Hz); 3.28 30% 296.3 (100%), (1.1 H, s); 3.38 (0.9 H, s); 3.44 (1.1 H, t, J = 7.1 Hz); 3.52 (0.9 H, t, R_(t) = 2.9 min. J = 7.3 Hz); 7.20-7.29 (1 H, m); 7.32-7.43 (4 H, m). ¹³C-NMR (CDCl₃): 18.75; 18.76; 28.58; 28.62; 30.7; 30.9; 32.3; 32.4; 34.0; 35.5; 40.3; 41.2; 41.7; 42.3; 44.0; 45.3; 56.7; 57.2; 57.3; 58.2; 126.1; 126.2; 126.4; 128.2; 128.3; 171.1. 423 1 Ex. no. 74/ m/z: [M + H]⁺ = ¹H-NMR (CDCl₃): 0.96 (3 H, d, J = 2.1 Hz); 0.97 (3 H, d, J = 2.1 Hz); N-Demethyl- 335.3 (46%) 1.34-1.52 (3 H, m); 1.63-1.73 (3 H, m); 1.74-1.80 (1 H, m); 1.80- ation/ [MH − H2NMe]+ = 1.90 (2 H, m); 1.95-2.10 (2 H, m); 2.12 (3 H, d, J = 2.2 Hz); 2.13- 33% 304.2 (100%), 2.15 (2 H, m); 2.15-2.23 (1 H, m); 3.30 (1.1 H, s); 3.36 (0.9 H, s); R_(t) = 2.9 min. 3.49 (2 H, td, J = 13.9, 7.2 Hz); 6.88-6.91 (1 H, m); 6.94-6.98 (1 H, m); 7.20-7.24 (1 H, m). ¹³C-NMR (CDCl₃): 22.7; 22.8; 25.59; 25.62; 28.6; 28.7; 30.8; 30.9; 34.2; 40.2; 42.3; 43.3; 43.7; 44.0; 45.3; 563.; 56.7; 56.8; 57.8; 132.7; 123.8; 126.3; 126.4; 171.5. * 1 = polar, 2 = non-polar, 3 = a diastereomer

Investigations of the Activity of the Compounds According to the Invention Measurement of the ORL1 Binding

The compounds were investigated in a receptor binding assay with ³H-nociceptin/orphanin FQ with membranes from recombinant CHO-ORL1 cells. This test system was conducted in accordance with the method described by Ardati et al. (Mol. Pharmacol., 51, 1997, p. 816-824). The concentration of ³H-nociceptin/orphanin FQ in these experiments was 0.5 nM. The binding assays were carried out with in each case 20 μg of membrane protein per 200 μl batch in 50 mM hepes, pH 7.4, 10 mM MgCl₂ and 1 mM EDTA. The binding to the ORL1 receptor was determined using in each case 1 mg of WGA-SPA beads (Amersham-Pharmacia, Freiburg) by incubation of the batch at RT for one hour and subsequent measurement in a Trilux scintillation counter (Wallac, Finland). The affinity is stated in Table 1 as the nanomolar K₁ value in or % inhibition at c=1 μM.

Measurement of the μ Binding

The receptor affinity for the human μ opiate receptor was determined in a homogeneous set-up in microtitre plates. For this, dilution series of the compound to be tested in each case were incubated with a receptor membrane preparation (15-40 μg of protein per 250 μl of incubation batch) of CHO-K1 cells which express the human μ opiate receptor (RB-HOM receptor membrane preparation from NEN, Zaventem, Belgium) in the presence of 1 nmol/l of the radioactive ligand [³H]-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mg of WGA-SPA-Beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia, Freiburg, Germany) in a total volume of 250 μl for 90 minutes at room temperature. 50 mmol/l of Tris-HCl supplemented with 0.05 wt. % of sodium azide and with 0.06 wt. % of bovine serum albumin was used as the incubation buffer. 25 μmol/1 of naloxone were additionally added for determination of the non-specific binding. After the end of the ninety-minute incubation time, the microtitre plates were centrifuged for 20 minutes at 1,000 g and the radioactivity was measured in a β-counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human μ opiate receptor was determined at a concentration of the test substances of 1 μmol/1 and stated as the percentage inhibition (% inhibition) of the specific binding. Starting from the percentage displacement by various concentrations of the substances of the general formula I to be tested, IC₅₀ inhibitory concentrations which cause a 50 percent displacement of the radioactive ligand were calculated in some cases. By conversion by means of the Cheng-Prusoff relationship, Ki values for the test substances were obtained. In some cases determination of the Ki value was dispensed with and only the inhibition at a test concentration of 1 μM was determined.

Testing of Analgesia in the Tail Flick Test in Rats

The analgesic activity of the test compounds was investigated in the focal ray (tail flick) test in rats in accordance with the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941)). Female Sprague Dawley rats weighing between 130 and 190 g were used for this. The animals were placed individually in special test cages and the base of the tail was exposed to a focused heat ray of a lamp (Tail-flick type 50/08/1.bc, Labtec, Dr Hess). The intensity of the lamp was adjusted such that in the case of untreated animals the time between switching on of the lamp to sudden pulling away of the tail (pain latency) was 2.5-5 seconds. Before administration of a test compound, the animals were pretested twice in the course of 30 minutes and the mean of these measurements was calculated as the pretest mean The pain was measured 20, 40 and 60 min after intravenous administration. The analgesic action was determined as the increase in pain latency (% MPE) according to the following formula: [(T₁−T₀)/(T₂−T₀)]×100. In this, T₀ is the latency period before and T₁ the latency period after administration of the substance, T₂ is the maximum exposure time (12 sec). To determine the dose dependency, the particular test compound was administered in 3-5 logarithmically increasing doses, which included the threshold and the maximum active dose in each case, and the ED₅₀ values were determined with the aid of regression analysis. The ED₅₀ calculation was performed at the action maximum, 20 minutes after intravenous administration of the substance.

Chung Model: Mononeuropathy Pain Following Spinal Nerve Ligation Animals:

Male Sprague Dawley rats (140-160 g), from a commercial breeder (Janvier, Genest St. Isle, France), were kept under a 12:12 h light-dark rhythm. The animals were kept with food and tap water ad libitum. A pause of one week was maintained between delivery of the animals and the operation. After the operation the animals were tested several times over a period of 4-5 weeks, a wash-out time of at least one week being adhered to.

Description of the Model:

The left L5, L6 spinal nerves were exposed under pentobarbital narcosis (Narcoren®, 60 mg/kg i.p., Merial GmbH, Hallbergmoos, Germany) by removing a piece of the paravertebral muscle and a part of the left spinal process of the L5 lumbar vertebra. The spinal nerves L5 and L6 were carefully isolated and tied off with a firm ligature (NC-silk black, USP 5/0, metric 1, Braun Melsungen AG, Melsungen, Germany) (Kim and Chung 1992). After ligation the muscle and adjacent tissue were sewn up and the wound was closed by means of metal clamps.

After a recovery period of one week the animals were placed in cages with a wire floor for measurement of the mechanical allodynia. The withdrawal threshold was determined on the ipsi- and/or contralateral hind paw by means of an electronic von Frey filament (Somedic AB, Malmö, Sweden). The median of five stimulations gave one data point. The animals were tested 30 min before and at various times after administration of the test substance or vehicle solution. The data were determined as % maximum possible effect (% MPE) from the pretesting of the individual animals (=0% MPE) and the test values of an independent sham control group (=100% MPE). Alternatively, the withdrawal thresholds were shown in grams.

Statistical Evaluation:

ED₅₀ values and 95% confidence intervals were determined via semilogarithmic regression analysis at the point in time of the maximum effect. The data were analysed via a variance analysis with repeated measurements and a post hoc Bonferroni analysis. The group size was usually n=10.

REFERENCES

-   Kim, S. H. and Chung, J. M., An experimental model for peripheral     neuropathy produced by segmental spinal nerve ligation in the rat,     Pain, 50 (1992) 355-363.

Results

Tail flick rat, i.v. SNL rat, i.v. % Ki ED_(50rat) ED_(50rat) inhibition (ORL1) % Ki (μ) [μg/kg] or [μg/kg] or (ORL1) mean inhibition mean % MPE % MPE No. Diastereomer [1 μM] [μM] (μ) [1 μM] [μm] (@μg/kg) (@μg/kg) 1 1 9 26 1.06 nd nd 2 2 11.5 4 4.79 nd nd 3 1 15 31.5 1.83 nd nd 4 2 9 28.5 0.92 nd nd 5 1 15 33 1.45 nd nd 6 2 23.5 49 1.1 nd nd 7 1 16 2.16 37.5 1.59 nd nd 8 2 25 45.5 1.05 nd nd 9 2 92.5 0.17 7.4 0.0045 nd nd 10 1 27.67 2.02 67 0.41 nd nd 11 2 43.5 0.16 71.5 0.034 nd nd 12 2 74.33 0.12 100.5 0.0079 nd nd 13 3 13 34 1.885 nd nd 14 1 57.5 0.068 76.5 0.026 83%@1000 nd 15 2 37.5 0.49 50.5 0.22 nd nd 16 1 10 0 nd nd 17 3 19 28 0.895 nd nd 18 1 47 0.175 90 0.018 nd nd 19 1 70 0.08 85 0.044 nd nd 20 1 82.5 0.0096 98.5 0.00227 26 30 21 1 89.5 0.0029 98.5 0.0028 414 105 22 1 94 0.0008 98.5 0.00114 100%@1000 nd 23 1 58 0.068 84.5 0.05 nd nd 24 2 49.5 0.74 70 0.13 nd nd 25 2 43.5 0.21 65.5 0.17 nd nd 26 2 63 0.38 77.5 0.12 nd nd 27 1 21.67 61.5 1105 nd nd 28 2 49 0.15 70.5 0.2 nd nd 29 1 81.5 0.00585 93 0.0305 157 100 30 1 16.5 32 4.04 nd nd 31 1 57.5 1135 79.5 0.13 nd nd 32 1 77.5 0.0155 93.5 0.00765 6.54 44%@6.81 33 2 31 0.425 16 1.2 nd nd 34 2 57.5 0.805 41 12420 nd nd 35 1 91 0.039 98.5 0.00815 0%@100 nd 36 1 73.5 0.023 98.5 0.00805 nd nd 37 1 34.5 0.26 86.5 0.077 nd nd 38 1 26 0.15 86 0.045 nd nd 39 1 84.5 0.027 100.5 0.0048 100%@100 nd 40 1 34.5 0.15 80.5 0.125 nd nd 41 1 64.5 0.064 83.5 0.078 nd nd 42 1 63 60 nd nd 43 1 73 0.00845 0.00805 100%@100 nd 44 1 48 0.085 80.5 0.0115 nd nd 45 1 61 0.102 85 0.077 nd nd 46 1 94 0.00235 98 0.0048 3.53 28%@3 47 1 71.5 0.018 80.5 0.0465 5260 nd 48 1 94 99.5 3.36 nd 49 1 92.33 0.0145 98.5 0.00895 nd nd 50 1 97.5 0.00024 99.5 0.00037 94%@10 nd 51 1 98 0.00145 99 0.0015 nd nd 52 1 98 0.00052 101.5 0.0006 52.8 nd 53 1 97 0.0017 100 0.00102 63%@1000 nd 54 1 93.5 0.00044 100 0.0004 nd nd 55 1 43.5 0.105 87 0.047 nd nd 56 1 89 0.0034 99 0.00175 7.16 nd 57 1 64 0.0715 92 0.037 25%@100 nd 58 1 52.67 0.155 93.5 0.0535 nd nd 59 1 97 0.00116 99.5 0.00062 nd nd 60 1 77 0.036 93.5 0.0215 90%@1000 nd 61 1 78 0.02 96.5 0.00715 87%@100 nd 62 1 98 0.00072 99 0.00052 nd nd 63 1 76 0.0825 90.5 0.0365 nd nd 64 1 96 0.00205 100.5 0.0013 1.86 nd 65 1 89.5 0.0165 99.5 0.00305 nd nd 66 1 81.5 0.0185 99.5 0.00545 nd nd 67 1 92 0.00295 99.5 0.00107 14.6 nd 68 1 97.5 0.00073 100.5 0.00039 nd nd 69 1 97.5 0.00076 99.5 0.00035 nd nd 70 1 84.5 0.0305 94.5 0.022 nd nd 71 1 62.5 0.057 65.5 0.215 nd nd 72 1 81.5 0.00585 93 0.0305 nd nd 73 1 43 0.161 58.5 0.275 nd nd 74 1 80 0.00975 93 0.0065 40%@1000 nd 75 1 97 0.00111 99.5 0.00115 16.2 69%@21.5 76 1 96.5 0.00075 100.5 0.00104 15.2 65%@21.5 77 1 94.5 0.00247 99 0.00165 78.6 nd 78 1 86.5 97.5 nd nd 79 1 98.5 0.0003 100 0.00036 nd nd 80 1 60.5 0.24 90 0.0795 nd nd 81 1 78.5 0.054 92.5 0.064 55%@1000 nd 82 1 90 0.015 97.5 0.00935 0%@100 nd 83 1 97.5 0.00056 99.5 0.0004 8.03 nd 84 1 81 0.0215 95.5 0.0134 nd nd 85 1 94.5 0.0018 99.5 0.00113 16.3 nd 86 1 95.5 0.00045 101.5 0.00063 4.17 nd 87 1 96 0.00106 100 0.00075 0%@100 nd 88 3 72 0.0735 97.5 0.0125 nd nd 89 3 89 100 nd nd 90 1 86.5 0.03 97.5 0.026 nd nd 91 1 86.5 0.0068 95.5 0.00805 nd nd 92 3 41395 23 3585 nd nd 93 3 12 24108 92 0.0265 nd nd 94 3 35.5 0.8 102.5 0.0053 nd nd 95 3 46 0.44 96.5 0.0265 nd nd 96 3 57.5 0.275 103 0.0068 nd nd 97 3 67.5 94.5 nd nd 98 3 85 0.019 99.5 0.0096 nd nd 99 3 67.5 0.028 97 0.0052 100%@100 nd 100 3 45 0.185 86.5 0.052 nd nd 101 3 82.5 0.011 88.67 0.017 0%@1000 nd 102 3 94.5 0.00435 99.5 0.00465 nd nd 103 3 79 0.0295 99.5 0.00405 5.43 2.44 104 3 88.5 0.0155 98.5 0.00245 162 107 105 3 90 0.00625 99.5 0.00069 nd nd 106 1 78 0.62 65.5 1775 nd nd 107 2 13.5 54.5 0.95 nd nd 108 1 21.5 0.91 54 0.64 nd nd 109 2 8 6 nd nd 110 1 24.5 1.52 43.5 1.21 nd nd 111 2 0 5 nd nd 112 1 59.5 54 nd nd 113 2 38.5 1.34 44 2.54 nd nd 114 3 30 34 0.71 nd nd 115 3 28 0.6 65 0.17 nd nd 116 3 20 1.57 67.5 0.145 nd nd 117 3 15 31.5 2.55 nd nd 118 2 6.5 3.5 5.5 nd nd 119 1 29 23 3.57 nd nd 120 2 13 31 7.07 nd nd 121 1 26 1.51 58 0.23 nd nd 122 2 21 45 0.67 nd nd 123 1 22 1.88 71.5 0.15 nd nd 124 1 55 0.089 79.5 0.17 nd nd 125 1 87 0.0039 98 0.00615 7.09 nd 126 1 97 0.00088 99 0.00185 nd nd 127 2 30 0.36 25.5 3.97 nd nd 128 1 98 0.00042 100.5 0.00034 nd nd 129 2 47 0.022 51.5 0.36667 nd nd 130 1 90.5 0.00075 99 0.00064 nd nd 131 2 47 0.22 37 1.18 nd nd 132 1 91.5 0.00079 99 0.0014 nd nd 133 2 47.5 0.175 32 1.4 nd nd 134 1 87 98 100%@100 nd 135 2 47.5 0.195 35.5 1.51 nd nd 136 1 87.5 0.00135 100 0.00102 nd nd 137 2 43 0.475 44 0.595 100%@100 nd 138 1 74 0.0215 97 0.00705 30.1 nd 139 2 28.5 0.68 23 3.88 nd nd 140 2 34 0.235 44 1.25 nd nd 141 1 90.5 0.0027 97.5 0.0019 4.84 nd 142 1 85 0.00575 94 0.0074 126 96 143 2 33 0.35 24 1.38 nd nd 144 1 91 0.0041 99.5 0.00205 11.5 64%@21.5 145 2 53 0.0675 77 0.161 nd nd 146 1 80.5 0.016 94.5 0.03 nd nd 147 2 46 0.225 50.5 0.59 nd nd 148 1 78 0.032 91 0.0425 70%@1000 nd 149 2 22.5 0.785 54.5 3.41 nd nd 150 1 95 0.00205 99 0.0004 90%@10 nd 151 2 63 0.022 95 0.029 nd nd 152 1 14 1.2 42 0.885 nd nd 153 2 36.5 0.41 72 0.28 nd nd 154 2 45 0.19 63.5 0.145 nd nd 155 1 19 0.79 21.5 2.82 nd nd 156 2 86 0.006 98 0.0036 nd nd 157 1 24 0.805 11.5 4.77 nd nd 158 2 94 0.00056 100 0.00054 nd nd 159 1 31.5 0.0915 32.5 0.185 nd nd 160 1 33 0.455 44 1.13 nd nd 161 1 63 0.345 97 0.0535 nd nd 162 2 82 0.029 95 0.038 422 nd 163 2 93.5 0.0022 97 0.003 nd nd 164 1 39 0.28 73 0.365 nd nd 165 2 96 100 nd nd 166 1 76 0.101 83 0.17 nd nd 167 2 97 0.00071 100.67 0.00108 nd nd 168 1 37.5 0.235 70 2.06 nd nd 169 2 95.5 0.00103 102 0.0012 nd nd 170 1 56.5 0.0825 37 0.63 nd nd 171 2 91 0.0047 99 0.003 26.8 nd 172 1 39.5 0.083 35.5 0.63 nd nd 173 2 96.5 0.00032 97.5 0.00061 nd nd 174 1 49.5 0.135 28 1.67 nd nd 175 2 96 0.00395 99.5 0.0024 55 72%@46.4 176 1 63 0.1045 72 0.175 nd nd 177 2 97.33 0.00165 99.5 0.0012 100%@100 nd 178 1 82.5 0.0395 96.5 0.0185 nd nd 179 2 93 0.0067 99 0.0075 nd nd 180 1 49.5 0.18 66.5 0.3 nd nd 181 2 77 0.01015 91.5 0.044 nd nd 182 2 96.5 0.0013 97 0.00075 6.92 nd 183 1 39.5 0.3 23.5 0.795 nd nd 184 2 97 0.00066 95.5 0.0003 3.25 nd 185 1 49 0.1045 60.5 0.255 nd nd 186 2 98.5 0.00205 99.5 0.0032 nd nd 187 1 59 0.34 58.5 41579 nd nd 188 1 91.5 0.0026 98 0.0026 nd nd 189 1 77.5 0.0425 93.5 0.036 nd nd 190 1 57 0.18 85.5 0.049 nd nd 191 1 93 0.0015 98 0.00195 0%@100 nd 192 1 96 0.0007 97.5 0.00044 nd nd 193 1 89 0.0097 97 0.0061 nd nd 194 1 92.5 0.0023 98 0.00135 nd nd 195 1 93.5 0.0005 99.5 0.00053 100%@100 nd 196 1 71.5 95 nd nd 197 1 95.5 0.00046 99.5 0.00048 100%@100 nd 198 1 48.5 0.1025 87 0.084 nd nd 199 1 72 0.073 93 0.03 nd nd 200 1 89 0.0119 98.5 0.00325 nd nd 201 1 94 0.0067 97.5 0.0039 0%@100 nd 202 1 88.5 0.0125 98 0.0054 nd nd 203 1 97.33 0.00127 98 0.00072 nd nd 204 1 95 0.00063 98 0.00145 nd nd 205 1 48.5 0.185 82.5 0.0745 nd nd 206 1 79 0.035 92 0.0255 nd nd 207 1 94.5 0.00417 99.5 0.00475 nd nd 208 1 96 0.00205 100 0.00067 nd nd 209 1 60 0.1125 94 0.0315 nd nd 210 1 80 0.023 94.5 0.0108 nd nd 211 1 95.5 0.0053 99.5 0.00073 nd nd 212 1 82.5 0.01967 99.33 0.00305 nd nd 213 1 98 0.00034 101.5 0.00072 nd nd 214 2 41.5 0.23 79.5 0.0645 nd nd 215 2 42 0.305 59 0.285 nd nd 216 1 85 0.00955 98.5 0.00615 52%@100 nd 217 1 97 0.00115 100 0.0004 0.7 nd 218 2 50.5 0.185 76.5 0.165 nd nd 219 2 36 0.315 46 0.945 nd nd 220 1 99 0.0012 97 0.00041 nd nd 221 1 96.5 0.002 101 0.0048 nd nd 222 2 46.5 0.265 62 0.605 nd nd 223 1 55 0.082 90.5 0.052 nd nd 224 2 73.5 0.036 97 0.02 nd nd 225 1 49 0.23 63 0.545 nd nd 226 1 94 0.0035 98 0.00255 nd nd 227 1 81.5 0.0165 94 0.0175 nd nd 228 1 46 0.23 79 0.082 nd nd 229 1 66 0.025 87 0.0445 nd nd 230 2 96.5 0.00315 98.5 0.0013 nd nd 231 1 43 0.18 91.5 0.0585 nd nd 232 1 97.5 0.00285 97.5 0.0031 nd nd 233 1 96 0.00225 98.5 0.0013 nd nd 234 2 81.5 0.0225 99.5 0.00435 nd nd 235 1 98.5 0.00047 100.5 0.00044 1.44 nd 236 2 91.5 0.016 100 0.00155 nd nd 237 1 97.5 0.00058 99.5 0.00055 100%@10 nd 238 1 98 0.00095 103 0.00082 nd nd 239 1 98 0.00083 103.5 0.00069 nd nd 240 1 45 0.195 91 0.08 nd nd 241 2 89.5 0.015 99 0.00875 nd nd 242 1 38.5 0.45 51 0.87 nd nd 243 1 36 41518 78 0.12 nd nd 244 2 26 0.255 74.5 0.0985 nd nd 245 2 59.5 0.115 95 0.066 nd nd 246 2 40 0.205 87.5 0.034 nd nd 247 3 91.5 0.01015 98.5 0.00265 100%@100 nd 248 1 90.5 0.00875 100 0.0012 nd nd 249 1 88 0.0117 99 0.002 nd nd 250 2 94.5 0.0019 99.5 0.00079 nd nd 251 2 82 0.0215 87 0.054 nd nd 252 1 46.5 0.3 37.5 14.305 nd nd 253 1 97.5 0.00165 98.5 0.0025 nd nd 254 2 94.5 0.00875 94 0.0185 nd nd 255 1 37.5 0.26 58.5 4385 nd nd 256 2 70.5 0.064 97.33 0.00565 nd nd 257 3 89 0.01365 98 0.0028 nd nd 258 3 63.5 0.084 97.5 0.00465 nd nd 259 3 67 0.062 95.5 0.062 nd nd 260 2 90 0.00865 93.5 0.0535 nd nd 261 1 42.5 0.395 40 1.4 nd nd 262 2 98.5 0.00155 98 0.00067 6.6 nd 262 1 50.5 0.245 37 1.51 nd nd 264 2 96.5 0.00275 98.5 0.0034 36.7 nd 265 3 71 0.029 95.5 0.006 nd nd 266 3 91 0.00633 100 0.00145 nd nd 267 3 64 0.039 97.7 0.0016 nd nd 268 3 76.5 0.093 99 0.01225 nd nd 269 2 89.5 0.0125 93 0.01005 nd nd 270 1 33.5 0.31 34 1.16 nd nd 271 1 54 0.245 53.5 1.41 nd nd 272 1 91 0.00705 95.5 0.00745 nd nd 273 3 81 89 nd nd 274 2 0 0.00745 0 0.002 nd nd 275 2 92 0.0079 96.5 0.00435 nd nd 276 2 73.5 0.021 95 0.0165 nd nd 277 2 91 0.0064 99 0.0008 nd nd 278 2 88.5 0.0079 99 0.0014 nd nd 279 2 93 0.01225 98.5 0.0106 nd nd 280 2 93.5 0.0088 97 0.0076 nd nd 281 2 75.5 0.0635 99.5 0.0087 nd nd 282 2 19.5 1.38 67.5 0.295 nd nd 283 1 91.5 0.031 99.5 0.011 nd nd 284 1 92.5 0.0195 95.5 0.00765 nd nd 285 1 95 0.0034 99 0.00255 nd nd 286 2 88 0.02 99.5 0.0013 nd nd 287 2 83 0.027 99 0.00105 nd nd 288 2 87.5 0.00595 98.5 0.0046 nd nd 289 1 45.5 0.17 69 0.27 nd nd 290 2 82 0.019 97 0.00565 nd nd 291 3 0.5 1225 66 0.175 nd nd 292 3 69 0.163 98 0.0084 nd nd 293 2 43.5 0.265 92 0.029 nd nd 294 2 52.5 0.07733 95 0.0275 nd nd 295 1 89 0.018 98.5 0.00635 nd nd 296 1 87 0.0111 98 0.0053 nd nd 297 3 26 0.91 90 0.055 nd nd 298 3 85 0.0205 98 0.00305 nd nd 299 1 94.5 0.00395 101 0.06661 nd nd 300 1 92 0.0073 100 0.00155 nd nd 301 3 66 0.071 90.5 0.0495 nd nd 302 3 48 0.1225 83 0.06 nd nd 303 1 93 0.0051 97.5 0.007 nd nd 304 1 95 0.00445 99 0.0049 nd nd 305 1 93 0.00245 99.5 0.00093 nd nd 306 1 97 0.00114 96.5 0.00057 nd nd 307 1 14.5 0.535 19 0.54 nd nd 308 2 92 0.01005 99 0.00155 nd nd 309 1 94 0.00113 100 0.0015 nd nd 310 1 52 0.195 29.5 1.03 nd nd 311 2 95.5 0.0021 98 0.00125 nd nd 312 1 54.5 0.12 74.5 0.295 nd nd 313 2 92.5 0.00345 99.5 0.00415 nd nd 314 1 94 0.0011 100 0.00073 nd nd 315 1 90 0.01055 100 0.0045 19.4 nd 316 1 10.5 1.23 27 2.15 nd nd 317 2 92.5 0.0027 99 0.0015 nd nd 318 2 88.5 0.0092 97.5 0.00715 nd nd 319 2 91 0.005 96.5 0.005 nd nd 320 1 93 0.0019 99.5 0.0018 nd nd 321 1 52 0.086 83 0.1495 nd nd 322 2 97 0.00165 101 0.00138 nd nd 323 2 93 0.00275 98 0.00905 nd nd 324 2 95 0.00135 100 0.0024 nd nd 325 2 88 0.0084 95 0.013 nd nd 326 2 96 0.00375 97.5 0.0043 nd nd 327 1 93 0.00555 101.5 0.00155 nd nd 328 1 96 0.00325 99 0.0024 nd nd 329 1 92 0.0088 97.5 0.0059 nd nd 330 1 24 0.69 60 0.97 nd nd 331 2 91 0.0076 100 0.00165 nd nd 332 2 96 0.0018 104 0.0027 nd nd 333 1 96 0.0055 102.5 0.0024 nd nd 334 2 95.5 0.0021 101 0.0052 nd nd 335 2 95.5 0.0015 99 0.0043 nd nd 336 2 93.5 0.0035 101 0.0014 nd nd 337 2 91 0.0021 101.5 0.00041 nd nd 338 1 96.5 0.002 97.5 0.0026 nd nd 339 1 93 0.0046 101 0.001 nd nd 340 2 95.5 0.00175 99 0.00285 nd nd 341 2 90.5 0.00935 99 0.0013 nd nd 342 1 94 0.0021 99.5 0.0032 nd nd 343 1 66 0.0595 92 0.024 nd nd 344 2 95.5 0.00143 99.5 0.00135 nd nd 345 1 48.5 0.15 90.5 0.0655 nd nd 346 1 93.5 0.00435 101 0.00165 nd nd 347 2 95.5 0.013 99 0.0037 nd nd 348 2 94 0.013 98.5 0.0047 nd nd 349 2 96.5 0.0018 98 0.0036 nd nd 350 1 92 0.01 95 0.0019 nd nd 351 1 93.5 0.0098 98.5 0.0016 nd nd 352 1 82 0.047 93.5 0.031 nd nd 353 2 98.5 0.00046 100 0.00098 nd nd 354 1 99 0.00052 100.5 0.00044 nd nd 355 1 98.5 0.00047 100 0.00025 nd nd 356 1 65 0.0855 91.5 0.0235 nd nd 357 2 98 0.00061 100.5 0.00155 nd nd 358 1 94 0.0039 98.5 0.0039 nd nd 359 1 92 0.0076 98 0.0025 nd nd 360 1 85 0.019 96 0.013 nd nd 361 1 91 0.0032 99 0.00145 nd nd 362 1 94.5 0.00086 98.5 0.00083 nd nd 363 1 95.5 0.00086 101 0.00037 nd nd 364 1 61.5 0.044 90.5 0.017 nd nd 365 1 71.5 0.02 89.5 0.0205 nd nd 366 1 95 0.00064 99.5 0.00135 nd nd 367 1 66.5 0.0405 98 0.016 nd nd 368 1 60.5 0.058 96.5 0.01215 nd nd 369 1 88 0.0115 97.5 0.011 nd nd 370 2 93.5 0.00053 97.5 0.00043 nd nd 371 1 96 0.00073 99 0.00106 nd nd 372 1 95 0.00145 99 0.00125 nd nd 373 1 93.5 0.00037 100.5 0.00066 nd nd 374 1 96 0.00038 100.5 0.00057 nd nd 375 1 77 0.043 99 0.0135 nd nd 376 2 93 0.00199 99 0.0005 nd nd 377 2 90 0.0065 99.5 0.00405 nd nd 378 2 90.5 0.00525 98 0.00615 nd nd 379 1 58 0.1045 93.5 0.045 nd nd 380 1 79 0.01685 97.5 0.00635 nd nd 381 1 74 0.0275 96 0.0195 nd nd 382 1 87 0.07 99 0.00915 nd nd 383 1 78.5 0.0865 96 0.0135 nd nd 384 1 95.5 0.00945 99 0.00165 nd nd 385 1 74 0.055 99.5 0.00735 nd nd 386 2 96.5 0.00091 100.5 0.00098 1.45 nd 387 2 97 0.00077 100 0.00067 nd nd 388 1 76 0.03 97.33 0.00825 nd nd 389 1 20.5 0.405 90 0.051 nd nd 390 1 66.5 0.0545 96 0.0195 nd nd 391 1 23.5 0.355 92 0.037 nd nd 392 1 42 0.114 96.5 0.00635 nd nd 393 1 57.5 0.048 98.5 0.00225 nd nd 394 1 98 0.0015 100 0.00094 nd nd 395 1 96.5 0.0017 101 0.00056 nd nd 396 1 37 0.355 97.5 0.0115 nd nd 397 1 48.5 0.1485 98 0.00525 nd nd 398 1 55 0.098 99 0.0016 nd nd 399 1 0 20 5.77 nd nd 400 2 34 0.825 86 0.0515 nd nd 401 1 0 23 2.76 nd nd 402 2 34.5 0.51 89 0.038 nd nd 403 1 6.5 23.5 4.125 nd nd 404 2 52.5 0.1385 96.5 0.0063 nd nd 405 1 99.5 0.00034 101.5 0.00044 nd nd 406 1 5 31 4.65 nd nd 407 1 0.135 94.5 0.0099 nd nd 408 2 0.139 82.5 0.08 nd nd 409 2 1.27 78.5 0.081 nd nd 410 1 8 20.5 5.77 nd nd 411 1 0.1695 93 0.0225 nd nd 412 1 0.00051 102.5 0.00044 nd nd 413 2 0.0605 98 0.00345 nd nd 414 2 67.5 0.0665 83.5 0.0595 nd nd 415 2 46.5 0.245 81 0.0685 nd nd 416 2 53 0.165 87.5 0.069 nd nd 417 2 93.5 0.0022 99.5 0.0004 nd nd 418 1 72 0.049 99 0.00265 nd nd 419 1 44.5 0.12 92 0.0385 nd nd 420 1 92.5 0.00605 100.5 0.0013 nd nd 421 2 95.5 0.00129 99.5 0.00031 nd nd 422 1 73.5 0.01125 98.5 0.00265 nd nd 423 1 72 0.018 98 0.00415 nd nd 424 425 426 427 428 429 430 431 432 433 nd = not determined * 1 = polar, 2 = non-polar, 3 = a diastereomer

If the experimental data summarised in the above table give the appearance that individual compounds according to the invention have a comparatively only low receptor affinity, it cannot be concluded from this that these compounds are pharmacologically completely inactive. Rather, these measurement results are connected with the chiefly arbitrarily chosen test concentration of 1 μM. It can be assumed that at a correspondingly higher concentration, e.g. at 10 μM, significantly higher values would also be measured for the receptor affinity. 

1. A compound of the general formula (1)

wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ in each case independently of each other are chosen from the group consisting of —H, —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀ and —NHC(═O)N(R₀)₂; or Y₁ and Y₁′, or Y₂ and Y₂′, or Y₃ and Y₃′, or Y₄ and Y₄′ together represent ═O; X₁, X₂, X₂′, X₃ and X₃′ in each case independently of each other represent —H, —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —SR₅, —SO₂R₅, —S(═O)₂OR₅, —CN, —COOR₅, —CONR₅, —NR₆R₇, or —R₀; or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O; or X₁ and X₂, or X₂ and X₃ together represent —(CH₂)₂₋₈—, wherein individual hydrogen atoms can also be replaced by —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —CN or —C₁₋₆-aliphatic; or X₁ and X₁′, or X₂ and X₂′ or X₃ and X₃′ together represent a C₁₋₆-cycloaliphatic, wherein individual hydrogen atoms can also be replaced by —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —CN or —C₁₋₆-aliphatic; R₀ in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; R₁ and R₂ independently of each other represent —H or —R₀; or R₁ and R₂ together represent —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₈CH₂CH₂— or —(CH₂)₃₋₆—; R₃ represents —R₀; R₄ represents H or —Z—R₁₁, wherein Z can be absent or —C(═O)—, —S(═O)— or —S(═O)₂—, and R₁₁ represents —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl, wherein in the C₃₋₆-cycloalkyl group a ring carbon atom can be replaced by an oxygen atom and —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl can be unsubstituted, mono- or polysubstituted with substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —SH, —O—C₁₋₃-alkyl and —S—C₁₋₃-alkyl, wherein —C₁₋₃-alkyl can be substituted by one or more substituents from the group including the substituents —F, —Cl, —Br, —I, —CN, —OH, —SH; R₅ in each case independently represents —H or —R₀; R₆ and R₇ independently of each other represent —H or —R₀; or R₆ and R₇ together represent —CH₂CH₂OCH₂CH₂—, —CH₂CH₂NR₁₀CH₂CH₂— or —(CH₂)₃₋₆—; R₈ represents —H, —R₀ or —C(═O)R₀; R₁₀ represents —H or —C₁₋₆-aliphatic; wherein “aliphatic” in each case is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon radical; “cycloaliphatic” in each case is a saturated or mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic, mono- or multicyclic hydrocarbon radical; wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” is understood as meaning substitution of one or more hydrogen atoms by —F, —Cl, —Br, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)—OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)N(R₀)₂, —OH, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N⁺(R₀)₃, —N(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NHC(═O)NH₂, —NHC(═O)NHR₀, —NH—C(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂; “aryl” in each case independently represents a carbocyclic ring system having at least one aromatic ring, but without hetero atoms in this ring, wherein the aryl radicals can optionally be fused with further saturated, (partially) unsaturated or aromatic ring systems and each aryl radical can be unsubstituted or mono- or polysubstituted, wherein the substituents on aryl can be identical or different and can be in any desired and possible position of the aryl; “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the hetero atoms are identical or different and are nitrogen, oxygen or sulfur and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of substitution on the heterocycle the substituents can be identical or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system; wherein with respect to “aryl” and “heteroaryl”, “mono- or polysubstituted” is understood as meaning substitution once or several times of one or more hydrogen atoms of the ring system by substituents chosen from the group consisting of —F, —Cl, —Br, —I, —CN, —NO₂, —CHO, ═O, —R₀, —C(═O)R₀, —C(═O)H, —C(═O)OH, —C(═O)OR₀, —C(═O)NH₂, —C(═O)NHR₀, —C(═O)—N(R₀)₂, —OH, —O(CH₂)₁₋₂₀—, —OR₀, —OC(═O)H, —OC(═O)R₀, —OC(═O)OR₀, —OC(═O)NHR₀, —OC(═O)N(R₀)₂, —SH, —SR₀, —SO₃H, —S(═O)₁₋₂—R₀, —S(═O)₁₋₂NH₂, —NH₂, —NHR₀, —N(R₀)₂, —N(R₀)₃, —N⁺(R₀)₂O⁻, —NHC(═O)R₀, —NHC(═O)OR₀, —NH—C(═O)NH₂, —NHC(═O)NHR₀, —NHC(═O)N(R₀)₂, —Si(R₀)₃, —PO(OR₀)₂; wherein N ring atoms optionally present can in each case be oxidised (N-oxide); in the form of an individual stereoisomer or mixture thereof, the free compound and/or its physiologically acceptable salt and/or solvate.
 2. A compound as claimed in claim 1, wherein Y₁°, Y₂′, Y₃′ and Y₄′ each represent —H.
 3. A compound as claimed in claim 1, wherein R₀ in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂.
 4. A compound as claimed in claim 1, wherein R₃ represents —C₁₋₃-aliphatic, -aryl, -heteroaryl, —C₁₋₃-aliphatic-aryl, —C₁₋₃-aliphatic-heteroaryl or —C₁₋₃-aliphatic-C₅₋₆-cycloaliphatic; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂; and X₁, X₁′, X₂, X₂′, X₃, X₃′ in each case independently of each other represent —H, —F, —Cl, —Br, —I, —NO₂, —CF₃, —OR₅, —SR₅, —SO₂R₅, —S(═O)₂OR₅, —CN, —COOR₅, —CONR₅, —NR₆R₇, or —R₀; or one of the radicals X₁ and X₁′ represents H and the other represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-heteroaryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂; or X₁ and X₁′, or X₂ and X₂′, or X₃ and X₃′ together represent ═O; or X₁ and X₁′ together represent C₃₋₆-cycloalkyl, which can be unsubstituted or substituted by one or more substituents independently of each other selected from the group consisting of —F, —Cl, —Br, —OR₅, SR₅, C₁₋₃-alkyl or —CN.
 5. A compound as claimed in claim 1, wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ each represent —H.
 6. A compounds as claimed in claim 1, which has the general formula (3.1)


7. A compound as claimed in claim 1, wherein Y₁, Y₁′, Y₂, Y₂′, Y₃, Y₃′, Y₄ and Y₄′ each represent —H; X₁, X₁′, X₂, X₂′, X₃ and X₃′ represent H; or X₂ and X₂′, or X₃ and X₃′ together represent ═O; or X_(i) and X₁′ together represent a C₃₋₆-cycloalkyl; R₀ in each case independently represents —C₁₋₈-aliphatic, —C₃₋₁₂-cycloaliphatic, -aryl, -heteroaryl, —C₁₋₈-aliphatic-C₃₋₁₂-cycloaliphatic, —C₁₋₈-aliphatic-aryl, —C₁₋₈-aliphatic-heteroaryl, —C₃₋₈-cycloaliphatic-C₁₋₈-aliphatic, —C₃₋₈-cycloaliphatic-aryl or —C₃₋₈-cycloaliphatic-heteroaryl; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂; R₁ represents CH₃; R₂ represents —H or —CH₃; or R₁ and R₂ together form a ring and represent —(CH₂)₃₋₄—; and R₃ represents —C₁₋₈-aliphatic, -aryl, -heteroaryl, —C₁₋₃-aliphatic-aryl, —C₁₋₃-aliphatic-heteroaryl or —C₁₋₃-aliphatic-C₅₋₆-cycloaliphatic; wherein these are unsubstituted or mono- or polysubstituted by substituents independently of each other chosen from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂; R₄ represents H or —Z—R₁₁, wherein Z can be absent or —C(═O)—, and R₁₁ represents —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl, wherein in the C₃₋₆-cycloalkyl group a ring carbon atom can be replaced by an oxygen atom and —C₁₋₆-alkyl, —C₃₋₆-cycloalkyl or —C₁₋₃-alkyl-C₃₋₆-cycloalkyl can be unsubstituted, mono- or polysubstituted with substituents independently of each other selected from the group consisting of —F, —Cl, —Br, —I, —CN, —OH, —SH, —O—C₁₋₃-alkyl and —S—C₁₋₃-alkyl, wherein —C₁₋₃-alkyl can be substituted by one or more substituents from the group consisting of the substituents —F, —Cl, —Br, —I, —CN, —OH and —SH.
 8. A compound as claimed in claim 1, wherein R₁ and R₂ each represent —CH₃.
 9. A compound as claimed in claim 1, wherein R₃ is selected from the group consisting of phenyl, benzyl and 2-thienyl, in each case unsubstituted or mono- or polysubstituted by substituents independently of each other selected from the group consisting of —F, —Cl, —Br, —CN, —CH₃, —C₂H₅, —NH₂, —NO₂, —SH, —CF₃, OH, —OCH₃, —OC₂H₅ and —N(CH₃)₂.
 10. A compound as claimed in claim 1, wherein R₄ is selected from the group consisting of H, CH₃, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, iso-butyl, t-butyl, n-pentyl, s-pentyl, iso-pentyl,


11. A compound as claimed in claim 1, selected from the group consisting of: 1; 2 8-Benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one 3; 4 (8-Benzyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine 5; 6 (8-Benzyl-3-methyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine 7; 8 1-[8-Benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-3-yl]-ethanone 9-(8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine 10; 11-[8-Benzyl-8-(dimethylamino)-3-azaspiro[4.5]decan-3-yl]-butan-1-one 12 [8-Benzyl-3-(cyclopentylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 13 8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-4-one 14; 15 8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 16 8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-4-one 17 8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one 18; 25 Dimethyl-(8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine 19 Dimethyl-(3-methyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-amine 20 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-butan-1-one 21 (3-Butyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl)-dimethylamine 22 [3-(Cyclopentyl-methyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 23 8-(Dimethylamino)-8-thiophen-2-yl-2-azaspiro[4.5]decan-3-one 24a/b 8-(Dimethylamino)-8-thiophen-2-yl-2-azaspiro[4.5]decan-3-one 26 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-butan-1-one 27 (8-Benzyl-3-butyl-3-azaspiro[4.5]decan-8-y)-dimethylamine 28; 29 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-butan-1-one 30 8-(Dimethylamino)-8-(5-methyl-thiophen-2-yl)-3-azaspiro[4.5]decan-4-one 31 Dimethyl-[8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-amine 32 1-[8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-butan-1-one 33 3-Butyl-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4,5]decan-2-one 34 8-(Dimethylamino)-3-methyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 35 [3-Butyl-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 36 Cyclobutyl-[8-dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-methanone 37 Cyclopropyl-[8-dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-methanone 38 1-[8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-2-methylpropan-1-one 39 1-[8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-3-methylbutan-1-one 40 1-[8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-propan-1-one 41 [3-(2-Methoxyethyl)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 42 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-methoxyethanone 43 Cyclobutyl-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methanone 44 Cyclopropyl-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methanone 45 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-methylpropan-1-one 46 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-methylbutan-1-one 47 [3-(2-Methoxyethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 48 2-Cyclopropyl-1-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethanone 49 [3-(Cyclopropylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 50 2-Cyclobutyl-1-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethanone 51 [3-(2-Cyclopropylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 52 [3-(2-Cyclobutylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 53 [3-(Cyclobutylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 54 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-4-methylpentan-1-one 55 3-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethyl-3-oxopropionitrile 56 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-tetrahydrofuran-3-ylethanone 57 (8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-(oxetan-3-yl)-methanone 58 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decane-3-carbonyl)-cyclopropane-1-carbonitrile 59 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-4-methoxy-4-methylpentan-1-one 60 [8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-tetrahydropyran-4-ylmethanone 61 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decane-3-carbonyl]-cyclobutane-1-carbonitrile 62 3-Cyclopropyl-1-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-propan-1-one 63 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-methoxy-2-methylpropan-1-one 64 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-y]-2-tetrahydrofuran-2-ylethanone 65 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-4-hydroxy-4-methylpentan-1-one 66 [8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-(1-hydroxycyclobutyl)-methanone 67 1-[2-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-oxoethyl]-cyclopropane-1-carbonitrile 68 1-[2-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-oxoethyl]-cyclobutane-1-carbonitrile 69 3-Cyclobutyl-1-[8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-propan-1-one 70 Dimethyl-[3-(oxetan-3-yl-methyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 71 Dimethyl-(8-phenyl-3-azaspiro[4.5]decan-8-yl)-amine 72 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-butan-1-one 73 1-(8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-ethanone 74 (3-Butyl-8-phenyl-3-azaspiro[4.5]decan-8-yl)-dimethylamine 75 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-tetrahydrofuran-2-ylethanone 76 1-[2-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-oxoethyl]-cyclobutane-1-carbonitrile 77 1-[2-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-oxoethyl]-cyclopropane-1-carbonitrile 78 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-(oxetan-3-yl)-ethanone 79 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-4-methylpentan-1-one 80 3-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethyl-3-oxopropionitrile 81 [8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-tetrahydropyran-4-yl-methanone 82 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-4-hydroxy-4-methylpentan-1-one 83 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-4-methoxy-4-methylpentan-1-one 84 [8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-(1-hydroxycyclobutyl)-methanone 85 2-Cyclopropyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethanone 86 2-Cyclobutyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethanone 87 [3-(4-Methoxy-4-methylpentyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 88 1-[8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-butan-1-one 89 [3-Butyl-8-(5-chlorothiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 90 1-[8-Dimethylamino-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-butan-1-one 91 [3-Butyl-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 92 8-(Cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one 93 1-[8-(Cyclohexylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-butan-1-one 94 [3-Butyl-8-(cyclohexylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 95 1-[8-(Cyclopentylmethyl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-butan-1-one 96 [3-Butyl-8-(cyclopentylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 97 1-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-butan-1-one 98 (3-Butyl-8-cyclopentyl-3-azaspiro[4.5]decan-8-y)-dimethylamine 99 Cyclobutyl-(8-cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-methanone 100 (8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-cyclopropylmethanone 101 [8-Cyclopentyl-3-(cyclopropylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 102 [3-(Cyclobutylmethyl)-8-cyclopentyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 103 1-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-cyclopropylethanone 104 [8-Cyclopentyl-3-(2-cyclopropylethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 105 2-Cyclobutyl-1-(8-cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-ethanone 106; 107 [3-Butyl-8-(dimethylamino)-3-azaspiro[4.5]decan-8-yl]-phenylmethanone 108; 109 1-[8-(Azetidin-1-yl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-y]-butan-1-one 110; 111 1-[8-(Azetidin-1-yl)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-butan-1-one 112; 113 8-(Azetidin-1-yl)-3-butyl-8-phenyl-3-azaspiro[4.5]decane 114 8-Dimethylamino-3-methyl-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one 115 3-Butyl-8-dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one 116 3-(Cyclopentylmethyl)-8-dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-4-one 117 8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-4-one 118; 119 8-Benzyl-8-(dimethylamino)-3-methyl-3-azaspiro[4.5]decan-4-one 120; 121 8-Benzyl-3-butyl-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one 122; 123 8-Benzyl-3-(cyclopentylmethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-4-one 124 8-(Dimethylamino)-3-methyl-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 125 3-Butyl-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 126; 127 3-(Cyclopentylmethyl)-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 128; 129 3-(2-Cyclobutylethyl)-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 130; 131 3-(2-Cycloproprolethyl)-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 132; 133 3-(Cyclobutylmethyl)-8-(dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 134; 135 3-(Cyclopropylmethyl)-8-(diethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 136; 137 8-(Dimethylamino)-3-(2-tetrahydrofuran-2-ylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 138; 139 8-(Dimethylamino)-3-(tetrahydropyran-4-ylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 140; 141 8-(Dimethylamino)-3-(2-tetrahydrofuran-3-ylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 142; 143 8-(Dimethylamino)-3-[2-(oxetan-3-yl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 144; 145 1-[2-[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 146; 147 8-(Dimethylamino)-3-(oxetan-2-ylmethyl)-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 148; 149 8-(Dimethylamino)-3-(oxetan-3-ylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 150; 151 1-[2-[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 152; 153 8-(Dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 154; 155 8-(Dimethylamino)-3-methyl-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 156; 157 3-Butyl-8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 158; 159 3-(Cyclopentylmethyl)-8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 160 3-(Cyclopropylmethyl)-8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 161 3-(Cyclobutylmethyl)-8-(dimethylamino)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 162 8-(Dimethylamino)-3-methyl-8-phenyl-3-azaspiro[4.5]decan-2-one 163; 164 3-Butyl-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 165; 166 3-(Cyclopentylmethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 167; 168 3-(2-Cyclopropylethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 169; 170 3-(Cyclobutylmethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 171; 172 3-(Cyclopropylmethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 173; 174 3-(2-Cyclobutylethyl)-8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-2-one 175; 176 1-[2-[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 177; 178 1-[2-[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 179; 180 8-(Dimethylamino)-3-[(1-hydroxycyclobutyl)-methyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 181 8-(Dimethylamino)-3-(2-hydroxy-2-methylpropyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 182; 183 8-(Dimethylamino)-3-(3-methoxy-3-methylbutyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 184; 185 8-(Dimethylamino)-3-[2-(1-methoxycyclobutyl)-ethyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 186; 187 8-(Dimethylamino)-3-(3-hydroxy-3-methylbutyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 188 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-tetrahydrofuran-3-ylethanone 189 [8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-(oxetan-3-yl)-methanone 190 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-methoxy-2-methylpropan-1-one 191 [3(2-Cyclopropylethyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 192 [3-(2-Cyclobutylethyl-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 193 1-[[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclobutan-1-ol 194 1-[2-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 195 3-Cyclobutyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-propan-1-one 196 Dimethyl-[3-(oxetan-3-ylmethyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-amine 197 3-Cyclopropyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-propan-1-one 198 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decane-3-carbonyl]-cyclopropane-1-carbonitrile 199 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decane-3-carbonyl]-cyclobutane-1-carbonitrile 200 1-[2-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 201 Dimethyl-[8-phenyl-3-(2-tetrahydrofuran-3-ylethyl)-3-azaspiro[4.5]decan-8-yl]-amine 202 [3-(2-Methoxy-2-methylpropyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 203 [3-(3-Cyclobutyl-propyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 204 [3-(3-Cyclopropyl-propyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 205 [8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-(-hydroxycyclopropyl)-methanone 206 1-[[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropan-1-ol 207 1-[[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclobutan-1-ol 208 1-[2-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 209 [8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-(1-hydroxycyclopropyl)-methanone 210 1-[[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropan-1-ol 211 1-[2-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 212 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-2-(oxetan-3-yl)-ethanone 213 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-ethylpentan-3-ol 214 1-[8-(Dimethylamino)-8-(thiophen-2-ylmethyl)-3-azaspiro[4.5]decan-3-yl]-butan-1-one 215; 216 8-(Dimethylamino)-3-[(1-hydroxycyclobutyl)-methyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 217; 218 8-(Dimethylamino)-3-[2-(1-methoxycyclobutyl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 219; 220 8-(Dimethylamino)-3-(3-methoxy-3-methylbutyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 221; 222 8-(Dimethylamino)-3-(3-hydroxy-3-methylbutyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 223 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-hydroxy-2-methylpropan-1-one 224; 225 8-(Dimethylamino)-3-(2-hydroxy-2-methylpropyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 226 4-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-methylbutan-2-ol 227 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-methylpropan-2-ol 228 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-hydroxy-2-methylpropan-1-one 229 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-methylpropan-2-ol 230; 231 4-[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylbutyronitrile 232 4-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethyl-4-oxobutyronitrile 233 4-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethyl-4-oxobutyronitrile 234 8-Cyclopentyl-3-(2-cyclopropylethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 235 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-(1-methoxycyclobutyl)-ethanone 236 3-(2-Cyclobutylethyl)-8-cyclopentyl-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 237 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-y]-2-(1-methoxycyclobutyl)-ethanone 238 [3-[2-(1-Methoxycyclobutyl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 239 [3-[2-(1-Methoxycyclobutyl)-ethyl]-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 240 4-[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylbutyronitrile 241; 242 8-(Dimethylamino)-3-[2-(oxetan-3-yl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 243 8-Cyclopentyl-3-(2-cyclopropylethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 244 8-Cyclopentyl-8-(dimethylamino)-3-(oxetan-3-ylmethyl)-3-azaspiro[4.5]decan-2-one 245 1-[2-[8-Cyclopentyl-8-(dimethylamino)-2-oxo-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 246 8-Cyclopentyl-8-(dimethylamino)-3-[2-(oxetan-3-yl)-ethyl]-3-azaspiro[4.5]decan-2-one 247 1-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-(1-methoxycyclobutyl)-ethanone 248 4-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylbutyronitrile 249 4-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylbutyronitrile 250 4-[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylbutyronitrile 251; 252 8-(Dimethylamino)-3-(oxetan-3-ylmethyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 253 1-[2-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropan-1-ol 254; 255 8-(Dimethylamino)-3-[2-(oxetan-3-yl)-ethyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 256 1-[2-[8-Cyclopentyl-8-(dimethylamino)-2-oxo-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 257 [8-Cyclopentyl-3-[2-(1-methoxycyclobutyl)-ethyl]-3-azaspiro[4.5]decan-8-yl]-dimethylamine 258 4-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2,2-dimethylbutyronitrile 259 4-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2,2-dimethyl-4-oxobutyronitrile 260; 261 8-(Dimethylamino)-8-phenyl-3-(tetrahydrofuran-3-ylmethyl)-3-azaspiro[4.5]decan-2-one 262; 263 8-(Dimethylamino)-8-phenyl-3-(2-tetrahydrofuran-2-ylethyl)-3-azaspiro[4.5]decan-2-one 264 8-(Dimethylamino)-8-phenyl-3-(2-tetrahydrofuran-3-ylethyl)-3-azaspiro[4.5]decan-2-one 265 [8-Cyclopentyl-3-(tetrahydropyran-4-ylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 266 [8-Cyclopentyl-3-(3-methylbutyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 267 1-[2-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-ethyl]-cyclopropane-1-carbonitrile 268 1-[2-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-ethyl]-cyclobutane-1-carbonitrile 269; 270 8-(Dimethylamino)-8-phenyl-3-(tetrahydropyran-4-ylmethyl)-3-azaspiro[4.5]decan-2-one 271 8-(Dimethylamino)-8-phenyl-3-(2-tetrahydrofuran-3-ylethyl)-3-azaspiro[4.5]decan-2-one 272 4-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-methylbutan-2-o 273 [8-Cyclopentyl-3-(2-methylpropyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 274 3-(Cyclobutylmethyl)-8-cyclopentyl-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 275 3-(2-Cyclopropylethyl)-8-methylamino-8-phenyl-3-azaspiro[4.5]decan-2-one 276 8-Cyclopentyl-3-(cyclopropylmethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 277 3-(Cyclohexylmethyl)-8-cyclopentyl-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 278 8-Cyclopentyl-3-(cyclopentylmethyl)-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 279; 280 8-(Dimethylamino)-3-[[(3S)-tetrahydrofuran-3-yl]-methyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 281 3-Butyl-8-cyclopentyl-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 282 8-Cyclopentyl-8-(dimethylamino)-3-methyl-3-azaspiro[4.5]decan-2-one 283 Dimethyl-[3-[2-(oxetan-3-yl)-ethyl]-8-phenyl-3-azaspiro[4.5]decan-8-yl]-amine 284 Dimethyl-[8-phenyl-3-(tetrahydrofuran-3-ylmethyl)-3-azaspiro[4.5]decan-8-yl]-amine 285 1-[2-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropan-1-ol 286 3,8-Dicyclopentyl-8-(dimethylamino)-3-azaspiro[4.5]decan-2-one 287 8-Cyclopentyl-8-(dimethylamino)-3-[2-(1-methoxycyclobutyl)-ethyl]-3-azaspiro[4.5]decan-2-one 288; 289 3-[8-(Dimethylamino)-2-oxo-8-thiophen-2-y-3-azaspiro[4.5]decan-3-y]-2,2-dimethylpropionitrile 290 3-(2-Cyclopropylethyl)-8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 291 (8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-(oxetan-3-yl)-methanone 292 [8-Cyclopentyl-3-(3-methoxy-3-methylbutyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 293; 294 8-Cyclopentyl-8-(dimethylamino)-3-[[(3S)-tetrahydrofuran-3-y]-methyl]-3-azaspiro[4.5]decan-2-one 295 Dimethyl-[3-[2-(oxetan-3-yl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 296 Dimethyl-[3-(tetrahydrofuran-3-ylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 297 1-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-methoxy-2-methylpropan-1-one 298 [8-Cyclopentyl-3-(2-methoxy-2-methylpropyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 299 [3-(3-Methoxy-3-methylbutyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 300 [3-(3-Methoxy-3-methylbutyl)-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 301 3-(8-Cyclopentyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-methylpropan-1-ol 302 [8-Cyclopentyl-3-(oxetan-3-ylmethyl)-3-azaspiro[4.5]decan-8-yl]-dimethylamine 303 Dimethyl-[8-phenyl-3-(tetrahydropyran-4-ylmethyl)-3-azaspiro[4.5]decan-8-yl]-amine 304 Dimethyl-[3-(tetrahydropyran-4-ylmethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 305 Dimethyl-[8-phenyl-3-(2-tetrahydrofuran-2-ylethyl)-3-azaspiro[4.5]decan-8-yl]-amine 306 Dimethyl-[3-(2-tetrahydrofuran-2-ylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 307; 308 3-(2-Cyclobutylethyl)-8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 309 Dimethyl-[3-(2-tetrahydrofuran-3-ylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-amine 310 3-(8-Dimethylamino-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl)-2,2-dimethylpropionitrile 311 8-Dimethylamino-3-[(1-methoxycyclobutyl)-methyl]-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 312 8-Dimethylamino-3-[(1-methoxycyclobutyl)-methyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 313 8-Dimethylamino-3-(2-ethoxyethyl)-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 314 1-(8-Dimethyl amino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-y)-3-methoxy-3-methylbutan-1-one 315 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-3-methoxypropan-1-one 316 3-(2-Cyclopropylethyl)-8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 317 8-(Dimethylamino)-3-(3-methoxybutyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 318 8-(Dimethylamino)-3-(2-methoxypropyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 319 3-[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2,2-dimethylpropionitrile 320 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-y]-3-methoxy-3-methylbutan-1-one 321 8-(Dimethylamino)-3-[(1-methoxycyclobutyl)-methyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 322 8-(Dimethylamino)-3-[(1-methoxycyclobutyl)-methyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 323 8-(Dimethylamino)-3-(2-methoxypropyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 324 8-(Dimethylamino)-3-(3-methoxybutyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 325 8-(Dimethylamino)-3-(2-methoxyethyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 326 8-(Dimethylamino)-3-(2-ethoxyethyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 327 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-methoxybutan-1-one 328 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-methoxybutan-1-one 329 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-y]-3-methoxypropan-1-one 330 3-(2-Cyclopropylethyl)-8-methylamino-8-phenyl-3-azaspiro[4.5]decan-2-one 331 3-(2-Cyclobutylethyl)-8-methylamino-8-phenyl-3-azaspiro[4.5]decan-2-one 332 8-(Dimethylamino)-3-(2-methoxy-2-methylpropyl)-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 333 2-Cyclobutyl-1-(8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-ethanone 334 8-(Dimethylamino)-3-(2-ethoxypropyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 335 8-(Dimethylamino)-3-(2-ethoxypropyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 336 8-(Dimethylamino)-3-(3-methoxy-3-methylbutyl)-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-2-one 337 8-(5-Chlorothiophen-2-yl)-8-(dimethylamino)-3-(3-methoxy-3-methylbutyl)-3-azaspiro[4.5]decan-2-one 338 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-ethoxybutan-1-one 339 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-ethoxybutan-1-one 340 8-(Dimethylamino)-3-(2-methoxy-2-methylpropyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 341 3-[2-(1-Methoxycyclobutyl)-ethyl]-8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 342 Cyclobutyl-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methanone 343 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-methylpropan-1-one 344 1-[[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropane-1-carbonitrile 345 [8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-(1-methoxycyclopropyl)-methanone 346 [3-(2-Cyclobutylethyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-methylamine 347 8-(Dimethylamino)-3-(2-tetrahydropyran-4-ylethyl)-8-thiophen-2-y-3-azaspiro[4.5]decan-2-one 348 8-(Dimethylamino)-8-phenyl-3-(2-tetrahydropyran-4-ylethyl)-3-azaspiro[4.5]decan-2-one 349 1-[[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropane-1-carbonitrile 350 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-2-tetrahydropyran-4-ylethanone 351 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-2-tetrahydropyran-4-ylethanone 352 1-[[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropane-1-carbonitrile 353 1-[[8-(Dimethylamino)-2-oxo-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-y]-methyl]-cyclobutane-1-carbonitrile 354 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-(1-methoxycyclobutyl)-propan-1-one 355 1-[8-(Dimethylamino)-8-thiophen-2-y-3-azaspiro[4.5]decan-3-yl]-3-(1-methoxycyclobutyl)-propan-1-one 356 [8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-(1-methoxycyclopropyl)-methanone 357 1-[[8-(Dimethylamino)-2-oxo-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclobutane-1-carbonitrile 358 [3-[(1-Methoxycyclopropyl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 359 1-[[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclobutane-1-carbonitrile 360 1-[[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclopropane-1-carbonitrile 361 1-[[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-methyl]-cyclobutane-1-carbonitrile 362 1-[3-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-oxopropyl]-cyclobutane-1-carbonitrile 363 1-[3-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-oxopropyl]-cyclobutane-1-carbonitrile 364 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-cyclopropylethanone 365 Cyclopropyl-(8-dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-methanone 366 1-(8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-3-methylbutan-1-one 367 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-3-cyclopropylpropan-1-one 368 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-4-methoxy-4-methylpentan-1-one 369 [3-[(1-Methoxycyclopropyl)-methyl]-8-phenyl-3-azaspiro[4.5]decan-8-yl]-dimethylamine 370 8-(Dimethylamino)-3-(3-methylbutyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 371 1-[3-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-oxopropyl]-cyclopropane-1-carbonitrile 372 1-[3-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-oxopropyl]-cyclopropane-1-carbonitrile 373 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-y)-2-(1-methoxycyclopropyl)-ethanone 374 1-(8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-y)-2-(1-methoxycyclopropyl)-ethanone 375 1-(8-Butyl-8-dimethylamino-2-azaspiro[4.5]decan-2-yl)-2-cyclobutylethanone 376 8-Dimethylamino-3-(3-methylbutyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 377 8-Dimethylamino-3-(2-methylpropyl)-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 378 8-Dimethylamino-3-(2-methylpropyl)-8-phenyl-3-azaspiro[4.5]decan-2-one 379 (8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-2-yl)-[1-(methoxymethyl)-cyclopropyl]-methanone 380 1-(8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-2-yl)-3-methoxy-2,2-dimethylpropan-1-one 381 (8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-2-yl)-[1-(methoxymethyl)-cyclobutyl]-methanone 382 (8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-(1-methoxycyclobutyl)-methanone 383 (8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-[1-(methoxymethyl)-cyclopropyl]-methanone 384 1-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-3-methoxy-2,2-dimethylpropan-1-one 385 (8-Dimethylamino-8-thiophen-2-y-3-azaspiro[4.5]decan-3-yl)-[1-(methoxymethyl)-cyclobutyl]-methanone 386 8-Dimethylamino-3-[2-(1-methoxycyclopropyl)-ethyl]-8-thiophen-2-yl-3-azaspiro[4.5]decan-2-one 387 8-Dimethylamino-3-[2-(1-methoxycyclopropyl)-ethyl]-8-phenyl-3-azaspiro[4.5]decan-2-one 388 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-(1-methoxycyclobutyl)-ethanone 389 1-(8-Butyl-8-dimethylamino-3-azaspiro[4.5]decan-3-yl)-2-tetrahydrofuran-3-ylethanone 390 (8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-(1-methoxycyclobutyl)-methanone 391 [8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-[1-(methoxymethyl)-cyclopropyl]-methanone 392 [8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-[1-(methoxymethyl)-cyclobutyl]-methanone 393 1-[8-Dimethylamino-8-(5-methylthiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-3-methoxy-2,2-dimethylpropan-1-one 394 5-(8-Dimethylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-2,2-dimethyl-5-oxopentanenitrile 395 5-(8-Dimethylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-azaspiro[4.5]decan-3-yl)-2,2-dimethyl-5-oxopentanenitrile 396 [8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-[1-(methoxymethyl)-cyclopropyl]-methanone 397 [8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-[1-(methoxymethyl)-cyclobutyl]-methanone 398 1-[8-(5-Chlorothiophen-2-yl)-8-dimethylamino-3-azaspiro[4.5]decan-3-yl]-3-methoxy-2,2-dimethylpropan-1-one 399; 400 8-Butyl-8-(dimethylamino)-3-(2-tetrahydrofuran-3-ylethyl)-3-azaspiro[4.5]decan-2-one 401; 402 1-[2-[8-Butyl-8-(dimethylamino)-2-oxo-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclopropane-1-carbonitrile 403; 404 1-[2-[8-Butyl-8-(dimethylamino)-2-oxo-3-azaspiro[4.5]decan-3-yl]-ethyl]-cyclobutane-1-carbonitrile 405 1-[8-(Dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-3-(1-methoxycyclopropyl)-propan-1-one 406 8-Butyl-8-(dimethylamino)-3-[2-(1-methoxycyclobutyl)-ethyl]-3-azaspiro[4.5]decan-2-one 407 [8-(Dimethylamino)-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-[1-(methoxymethyl)-cyclobutyl]-methanone 408 2-Cyclopropyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethanone 409; 410 8-Butyl-8-(dimethylamino)-3-[2-(oxetan-3-yl)-ethyl]-3-azaspiro[4.5]decan-2-one 411 [8-(Dimethylamino)-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-3-y]-[1-(methoxymethyl)-cyclopropyl]-methanone 412 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-(1-methoxycyclopropyl)-propan-1-one 413 8-Butyl-8-(dimethylamino)-3-[2-(1-methoxycyclobutyl)-ethyl]-3-azaspiro[4.5]decan-2-one 414 2-Cyclobutyl-1-[8-(dimethylamino)-8-phenyl-3-azaspiro[4.5]decan-3-yl]-ethanone 415 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-methoxy-propan-1-one 416 1-[8-(Dimethylamino)-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl]-3-methylbutan-1-one 417 8-(Dimethylamino)-8-(5-fluorothiophen-2-y)-3-(3-methoxy-3-methylbutyl)-3-azaspiro[4.5]decan-2-one 418 1-[8-Dimethylamino-8-(5-fluorothiophen-2-yl)-3-azaspiro[4.5]decan-3-yl]-3-methoxy-3-methylbutan-1-one 419 3-Methoxy-1-(8-methylamino-8-thiophen-2-yl-3-azaspiro[4.5]decan-3-yl)-propan-1-one 420 2-Cyclobutyl-1-(8-methylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-ethanone 421 8-(Dimethylamino)-8-(5-fluorothiophen-2-yl)-3-[2-(1-methoxycyclopropyl)-ethyl]-3-azaspiro[4.5]decan-2-one 422 2-Cyclopropyl-l-(8-methylamino-8-phenyl-3-azaspiro[4.5]decan-3-yl)-ethanone 423 3-Methyl-1-(8-methylamino-8-thiophen-2-y-3-azaspiro[4.5]decan-3-yl)-butan-1-one 424 8-Cyclopentyl-8-dimethylamino-2-azaspiro[4.5]decane 425 8-(5-Chloro-2-thiophen-2-yl)-2-azaspiro[4.5]dec-8-yl]-dimethylamine 426 [8-(5-Fluorothiophen-2-yl)-2-azaspiro[4.5]dec-8-yl]-dimethylamine 427; 428 8-(Azetidin-l-yl)-8-(2-thienyl)-3-azaspiro[4.5]decane 429,430 8-Azetidin-1-yl-8-phenyl-2-azaspiro[4,5]decane 431 8-Dimethylamino-8-phenyl-2-azaspiro[4.5]decan-3-one 432; 433 8-Butyl-8-dimethylamino-2-azaspiro[4.5]decan-3-one in the form of an individual stereoisomer or mixture thereof, the free compound and/or its physiologically acceptable salt and/or solvate.
 12. A medicament containing at least one compound as claimed in claim 1 in the form of an individual stereoisomer or mixture thereof, the free compound and/or its physiologically acceptable salt and/or solvate, and optionally suitable additives and/or auxiliary substances and/or optionally further active compounds.
 13. A compound as claimed in claim 1 in the form of an individual stereoisomer or mixture thereof, the free compound and/or its physiologically acceptable salt and/or solvate for use in the treatment of pain.
 14. A method of treating anxiety states, of stress and syndromes associated with stress, depressions, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicament abuse and/or dependency, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, impaired hearing, lack of intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhoea, cachexia, urinary incontinence or as a muscle relaxant, anticonvulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or with an anaesthetic, for diuresis or antinatriuresis, anxiolysis, for modulation of motor activity, for modulation of neurotransmitter secretion and treatment of neurodegenerative diseases associated therewith, for treatment of withdrawal symptoms and/or for reduction of the addiction potential of opioids comprising administering a compound of claim
 1. 